Pharmaceutically active compounds and methods of use

ABSTRACT

The present invention relates to pharmaceutically acceptable compounds, including certain substituted indolinyl and derivatives thereof, 1,2,3,4-tetrahydroquinolinyl and derivatives thereof, 1,2,3,4-tetrahydroisoquinolinyl, benz[cd]indolinyl and 5,6-dihydrophenanthridinyl compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are particularly useful for the treatment or prophylaxis of neurological injury and neurodegenerative disorders.

This application is a 371 of PCT/US97/02678 filed Feb. 14, 1997 which isa continuation-in-part of U.S. application Ser. No. 08/601,992, filedFeb. 15, 1996, now abandoned which application is incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to pharmaceuticially active compounds,including certain substituted indolinyl (and derivatives thereof),1,2,3,4-tetrahydroquinolinyl (and derivatives thereof),1,2,3,4-tetrahydroisoquinolinyl, benz[cd]indolinyl and5,6-dihydrophenanthridinyl compounds, and methods of treatment andpharmaceutical compositions that utilize or comprise one or more suchcompounds. Compounds of the invention are particularly usefull for thetreatment or prophylaxis of neurological injury and neurodegenerativedisorders.

2. Background

Nerve cell death (degeneration) can cause potentially devastating andirreversible effects for an individual and may occur e.g. as a result ofstroke, heart attack or other brain or spinal chord ischemia or trauma.Additionally, neurodegenerative disorders involve nerve cell death(degeneration) such as Alzheimer's disease, Parkinson's disease,Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome andKorsakoff's disease.

Therapies have been investigated to treat nerve cell degeneration andrelated disorders, e.g., by limiting the extent of nerve cell death thatmay otherwise occur to an individual. See, e.g., N. L. Reddy et al., J.Med. Chem., 37:260-267 (1994); and WO 95/20950.

The compound MK-801 has exhibited good results in a variety of in vivomodels of stroke. See B. Meldrum, Cerbrovascular Brain Metab. Rev.,2:27-57 (1990); D. Choi, Cerbrovascular Brain Vetab. Rev., 2:105-147(1990). See also Merck Index, monograph 3392, 11th ed., 1989. Forexample, MK-801 exhibits good activity in mouse audiogenic tests, arecognized model for evaluation of neuroprotective drugs. See, e.g. M.Tricklebank et al., European Journal of Pharnacology, 167:127-135(1989); T. Seyfried, Federation Proceedings, 38(10):2399-2404 (1979).

However, MK-801 also has shown toxicity and further clinical developmentof the compound is currently uncertain. See J. W. Olney et al., Science,244:1360-1362 (1989); W. Koek et al., J. Pharmacol. Exp. Ther.,252:349-357 (1990); F. R. Sharp et al., Society for Neuroscience Abstr.,abstr. no. 482.3 (1992).

It thus would be highly desirable to have new neuroprotective agents,particularly agents to limit the extent or otherwise treat nerve celldeath (degeneration) such as may occur with stroke, heart attack orbrain or spinal cord trauma, or to treat neurodegenerative disorderssuch as Alzheimer's disease, Parkinson's disease, Huntington's disease,Amyotrophic Lateral Sclerosis, Down's Syndrome and Korsakoffs disease.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides substituted indolinyland indolinyl derivative compounds of the following Formula I: ##STR1##wherein R and R¹ are each independently hydrogen; substituted orunsubstituted alkyl having from 1 to about 20 carbon atoms; substitutedor unsubstituted alkenyl having from 2 to about 20 carbon atoms;substituted or unsubstituted alkynyl having from 2 to about 20 carbonatoms; substituted or unsubstituted alkoxy having from 1 to about 20carbon atoms; substituted or unsubstituted alkylthio having from 1 toabout 20 carbon atoms; substituted or unsubstituted aminoalkyl havingfrom 1 to about 20 carbon atoms; substituted or unsubstitutedalkylsulfinyl having 1 to about 20 carbon atoms; substituted orunsubstituted alkylsulfonyl having 1 to about 20 carbon atoms;substituted or unsubstituted carbocyclic aryl having at least about 6ring carbon atoms; or a substituted or unsubstituted heteroaromatic orheteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members ineach ring and from 1 to 3 hetero atoms, with at least one of R and R¹being other than hydrogen;

each R² and each R³ (i.e. substituent of the 4, 5, 6 and 7 aromatic ringpositions) are each independently hydrogen, halogen, hydroxyl, azido,substituted or unsubstituted alkyl having from 1 to about 20 carbonatoms, substituted or unsubstituted alkenyl having from 2 to about 20carbon atoms, substituted or unsubstituted alkynyl having from 2 toabout 20 carbon atoms, substituted or unsubstituted alkoxy having from 1to about 20 carbon atoms, substituted or unsubstituted alkylthio having1 to about 20 carbon atoms, substituted or unsubstituted aklsulfmylhaving from 1 to about 20 carbon atoms, substituted or unsubstitutedalkylsulfonyl having from 1 to about 20 carbon atoms, substituted orunsubstituted aninoalkylo having from 1 to about 20 carbon atoms,substituted or unsubstituted carbocyclic aryl having at least about 6ring carbon atoms, or substituted or unsubstituted aralkyl having atleast about 6 ring carbon atoms;

X is substituted or unsubstituted methylene (--CH₂ --), --S-- (i.e.3-benzothiazolinylcarboximidamide compounds), --O-- or substituted orunsubstituted --N--, and preferably is substituted or unsubstitutedmethylene;

m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and pharmaceutically acceptablesalts thereof.

In a further aspect, the invention provides compounds of the followingFormula II: ##STR2## wherein R and R¹ are each independently hydrogen;substituted or unsubstituted alkyl having from 1 to about 20 carbonatoms; substituted or unsubstituted alkenyl having from 2 to about 20carbon atoms; substituted or unsubstituted alkynyl having from 2 toabout 20 carbon atoms; substituted or unsubstituted alkoxy having from 1to about 20 carbon atoms; substituted or unsubstituted alkylthio havingfrom 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkylhaving from 1 to about 20 carbon atoms; substituted or unsubstitutedalkylsulfinyl having 1 to about 20 carbon atoms; substituted orunsubstituted alkylsulfonyl having 1 to about 20 carbon atoms;substituted or unsubstituted carbocyclic aryl having at least about 6ring carbon atoms; or a substituted or unsubstituted heteroaromatic orheteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members ineach ring and from 1 to 3 hetero atoms;

each R² (i.e. substituent of the 2 and 3 ring positions) and each R³(i.e. substituent of the 5, 6, 7 and 8 aromatic ring positions) are eachindependently hydrogen, halogen, hydroxyl, azido, substituted orunsubstituted alkyl having from 1 to about 20 carbon atoms, substitutedor unsubstituted alkenyl having from 2 to about 20 carbon atoms,substituted or unsubstituted alkynyl having from 2 to about 20 carbonatoms, substituted or unsubstituted alkoxy having from 1 to about 20carbon atoms, substituted or unsubstituted alkylthio having 1 to about20 carbon atoms, substituted or unsubstituted aksulfmyl having from 1 toabout 20 carbon atoms, substituted or unsubstituted alkylsulfonyl havingfrom 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkylhaving from 1 to about 20 carbon atoms, substituted or unsubstitutedcarbocyclic aryl having at least about 6 ring carbon atoms, orsubstituted or unsubstituted aralkyl having at least about 6 ring carbonatoms;

X is --O-- (i.e. 2,3-benzmorpholinyl compounds), --S-- (i.e.2,3-benzthiomorpholinyl compounds), substituted or unsubstituted --N--,or substituted or unsubstituted methylene (--CH₂ --);

m and n are each independently 0 (i.e. the available ring are eachhydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically acceptablesalts thereof.

In a still further aspect, the invention providestetrahydroisoquinolinyl compounds of the following Formula III: ##STR3##wherein R and R¹ are each independently hydrogen; substituted orunsubstituted alkyl having from 1 to about 20 carbon atoms; substitutedor unsubstiruted alkenyl having from 2 to about 20 carbon atoms;substituted or unsubstituted alkynyl having from 2 to about 20 carbonatoms; substituted or unsubstituted alkoxy having from 1 to about 20carbon atoms; substituted or unsubstituted alkylthio having from 1 toabout 20 carbon atoms; substituted or unsubstituted alkylthio havingfrom 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkylhaving from 1 to about 20 carbon atoms; substituted or unsubstitutedalkylsulfinyl having 1 to about 20 carbon atoms; substituted orunsubstituted alkylsulfonyl having 1 to about 20 carbon atoms;substituted or unsubstituted carbocyclic aryl having at least about 6ring carbon atoms; or a substituted or unsubstituted heteroaromatic orheteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members ineach ring and from 1 to 3 hetero atoms;

each R² (i.e. substituent of the 1, 3 and 4 tetrahydroisoquinolinyl ringpositions) and each R³ (i.e. substituent of the 5, 6, 7 and 8tetrahydroisoquinolinyl ring positions) are each independently hydrogen,halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from1 to about 20 carbon atoms, substituted or unsubstituted alkenyl havingfrom 2 to about 20 carbon atoms, substituted or unsubstituted alkynylhaving from 2 to about 20 carbon atoms, substituted or unsubstitutedalkoxy having from 1 to about 20 carbon atoms, substituted orunsubstituted alkylthio having 1 to about 20 carbon atoms, substitutedor unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms,substituted or unsubstituted alkylsulfonyl having from 1 to about 20carbon atoms, substituted or unsubstituted aminoalkyl having from 1 toabout 20 carbon atoms, substituted or unsubstituted carbocyclic arylhaving at least about 6 ring carbon atoms, or substituted orunsubstituted aralkyl having at least about 6 ring carbon atoms;

m is 0 (i.e. the 1, 3 and 4 tetrahydroisoquinolinyl ring positions areeach hydrogen-substituted), 1, 2, 3, 4, 5 or 6; n is 0 (i.e. the 5, 6, 7and 8 tetrahydroisoquinolinyl ring positions are eachhydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically acceptablesalts thereof.

In a yet further aspect, the invention provides compounds of thefollowing Formula IV: ##STR4## wherein R and R¹ are each independentlyhydrogen; substituted or unsubstituted alkyl having from 1 to about 20carbon atoms; substituted or unsubstituted alkenyl having from 2 toabout 20 carbon atoms; substituted or unsubstituted alkynyl having from2 to about 20 carbon atoms; substituted or unsubstituted alkoxy havingfrom 1 to about 20 carbon atoms; substituted or unsubstituted alkylthiohaving from 1 to about 20 carbon atoms; substituted or unsubstitutedaminoalkyl having from 1 to about 20 carbon atoms; substituted orunsubstituted alkylsulfinyl having 1 to about 20 carbon atoms;substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbonatoms; substituted or unsubstituted carbocyclic aryl having at leastabout 6 ring carbon atoms; or a substituted or unsubstitutedheteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8ring members in each ring and from 1 to 3 hetero atoms, with at leastone of R and R¹ being other than hydrogen;

each R² and each R³ (i.e. substituent of the aromatic positions 3-8) areeach independently hydrogen, halogen, hydroxyl, azido, substituted orunsubstituted alkyl having from 1 to about 20 carbon atoms, substitutedor unsubstituted alkenyl having from 2 to about 20 carbon atoms,substituted or unsubstituted alkynyl having from 2 to about 20 carbonatoms, substituted or unsubstituted alkoxy having from 1 to about 20carbon atoms, substituted or unsubstituted alkylthio having 1 to about20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonylhaving from 1 to about 20 carbon atoms, substituted or unsubstitutedaminoalkyl having from 1 to about 20 carbon atoms, substituted orunsubstituted carbocyclic aryl having at least about 6 ring carbonatoms, or substituted or unsubstituted aralkyl having at least about 6ring carbon atoms;

m is 0 (i.e. the 2-benz[cd]indolinyl position is hydrogen-substituted),1 or 2; and n is 0 (i.e. the available ring are eachhydrogen-substituted), 1, 2, 3, 4, 5 or 6; and pharmaceuticallyacceptable salts thereof.

Still further, the invention provides compounds of the following FormulaV: ##STR5## wherein R and R¹ are each independently hydrogen;substituted or unsubstituted alkyl having from 1 to about 20 carbonatoms; substituted or unsubstituted alkenyl having from 2 to about 20carbon atoms; substituted or unsubstituted alkynyl having from 2 toabout 20 carbon atoms; substituted or unsubstituted alkoxy having from 1to about 20 carbon atoms; substituted or unsubstituted alkylthio havingfrom 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkylhaving from 1 to about 20 carbon atoms; substituted or unsubstitutedalkylsulfinyl having 1 to about 20 carbon atoms; substituted orunsubstituted alkylsulfonyl having 1 to about 20 carbon atoms;substituted or unsubstituted carbocyclic aryl having at least about 6ring carbon atoms; or a substituted or unsubstituted heteroaromatic orheteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members ineach ring and from 1 to 3 hetero atoms, with at least one of R and R¹being other than hydrogen;

each R², each R³ (i.e. substituent of the aromatic positions 1-4) andeach R⁴ (i.e. substituent of the aromatic positions 7-10) are eachindependently hydrogen, halogen, hydroxyl, azido, substituted orunsubstituted aLlyl having from 1 to about 20 carbon atoms, substitutedor unsubstituted alkenyl having from 2 to about 20 carbon atoms,substituted or unsubstituted allynyl having from 2 to about 20 carbonatoms, substituted or unsubstituted alkoxy having from 1 to about 20carbon atoms, substituted or unsubstituted alkylthio having 1 to about20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonylhaving from 1 to about 20 carbon atoms, substituted or unsubstitutedaminoalkyl having from 1 to about 20 carbon atoms, substituted orunsubstituted carbocyclic aryl having at least about 6 ring carbonatoms, or substituted or unsubstituted aralcyl having at least about 6ring carbon atoms;

m is 0 (i.e. the 5,6-dihydrophenanthridinyl ring position ishydrogen-substituted), 1 or 2; and n and r are each independently 0(i.e. the ring positions are each hydrogen-substituted), 1, 2, 3 or 4;and pharmaceutically acceptable salts thereof.

In a yet further aspect the invention provides compounds of thefollowing Formulae VI: ##STR6## wherein R, R¹, X, R², R³ and n are thesame as defined above for Formula II, but where X can also be sulfinyl(i.e. --S(O)--) or sulfonyl (i.e. --S(O₂)--), and m of Formula VI is aninteger equal to 0-6, and preferably m is 0, 1 or 2; andpharmaceutically acceptable salts thereof. Preferred substituents ofFormula II also will be preferred substituents at correspondingpositions of compounds of of Formula VI.

The invention also provides compounds of the following Formula VII:##STR7## wherein R, R¹, R², R³ and m are the same as defined above forFormula IV, and n of Formula VII is an integer equal to 0-9, andpreferably n is 0, 1 or 2; and pharmaceutically acceptable saltsthereof. It is understood that an R³ substituent can be the same ordifferent and may be present on either the non-aromatic or aromaticfused ring. Preferred substiments of Formula IV also will be preferredsubstituents at corresponding positions of compounds of Formula VI.

The invention also provides compounds of the following Formula VIII:##STR8## wherein R, R¹, R², R³, n and r are the same as defined abovefor Formula V, except R and R¹ each may be hydrogen, although preferablyat least one of R and R¹ will be other than hydrogen, and m of FormulaVIII is an integer equal to 0-4, and preferably m is 0, 1 or 2, and thedotted line in Formula VIII represents an optional carbon-carbon doublebond (endocyclic bond); and pharmaceutically acceptable salts thereof.Preferred substituents of Formula V also will be preferred substituentsat corresponding positions of compounds of Formula VIII.

The invention also provides compounds of the following Formula IX:##STR9## wherein R², R³, n and r are the same as defined above forFormula V; R and R¹ are also the same as defined above for Formula V,except R and R¹ each may be hydrogen, although preferably at least oneof R and R¹ will be other than hydrogen; m of Formula IX is an integerequal to 0-6 (i.e. R² may be a substituent at any of the available threesaturated ring positions), and preferably m is 0, 1 or 2

For each of Formulae I, II, III, IV and V, as well as for each ofFormulae VI, VII, VII and IX and Formulae I" and II" as defined below,preferably at least one of R and R¹ is a carbocyclic aryl, aralkyl, orheteroaromatic or heteroalicyclic group, particularly substituted orunsubstituted phenyl or naphthyl. More preferably, for each of FormulaeI through IX (which includes Formulae I" and II"), R is a carbocyclicaryl, heteroaromatic or heteroalicyclic group, and R¹ is a non-arylgroup, particularly hydrogen or substituted or unsubstituted alkyl,alkoxy, allylthio, alkylsulfinyl, alkylsulfonyl, or aminoalkyl.Substituted or unsubstituted phenyl or naphthyl are preferred R groupsof Formulae I through IX (including Formulae I" and II"). Generally morepreferred R¹ groups are hydrogen and substituted or unsubstituted alkylsuch as substituted or unsubstituted alkyl having 1 to about 6 carbonatoms or 1 to about 3 carbon atoms.

The compounds of the invention (i.e. compounds of Formulae I, II, III,IV and V as well as compounds of Formulae I', I", Ia, Iaa, Ib, II", IIa,IIaa, IIb, IIIa. Iaa, IIIb, IVa, IVaa, IVb, Va, Vaa and Vb as discussedbelow, and as well as compounds of Formulae VI, VII, VIII and IX above)are useful for a number of therapeutic applications. In particular, theinvention includes methods for treatment and/or prophylaxis ofneurological conditions/injuries such as epilepsy, neurodegenerativeconditions and/or nerve cell death (degeneration) resulting from e.g.hypoxia, hypoglycemia, brain or spinal chord ischemia, retinal ischemia,brain or spinal chord trauma or post-surgical neurological deficits andthe like as well as neuropathic pain. The compounds of the invention areespecially useful for treatment of a person susceptible or sufferingfrom stroke or heart attack or neurological deficits relating to cardiacarrest, a person suffering or susceptible to brain or spinal cordinjury, or a person suffering from the effects of retinal ischemica ordegeneration, or a person suffering from decreased blood flow ornutrient supply to retinal tissue or optic nerve or retinal trauma oroptic nerve injury. Compounds of the invention also are useful to treatand/or prevent various neurodegenerative diseases such as Parkinson'sdisease, Huntington's disease, Amyotrophic Lateral Sclerosis,Alzheimer's disease, Down's Syndrome, Korsakoff's disease, cerebralpalsy and/or age-dependent dementia. Compounds of the invention will befurther useful to treat and/or prevent migraines, shingles (herpeszoster), epilepsy, emesis and/or narcotic withdrawal symptoms. Thetreatment methods of the invention in general comprise administration ofa therapeutically effective amount of one or more compounds of theinvention to an animal, including a mammal, particularly a human.

Particularly preferred compounds of the invention exhibit good activityin an anticonvulsant in vivo mouse audiogenic assay e.g. as disclosed inExample 48 which follows, preferably about 20% or more inhibition at adose of a compound of the invention of 20 mg/kg, more preferably about50% or more or 70% or more inhibition at a dose of 20 mg/kg in such ananticonvulsant in vivo audiogenic assay.

The invention also provides pharmaceutical compositions that compriseone or more compounds of the invention and a suitable carrier for thecompositions.

Other aspects of the invention are disclosed infra.

DETAILED DESCR1PTION OF THE INVENTION

As mentioned above, preferred compounds of Formula I include those wherethe group X is substituted or unsubstituted methylene, i.e. indolinylcompounds of the following Formula I': ##STR10## where R, R¹, R², R³ andn are each the same as defmed above for Formula I; m is 0, 1, 2, 3 or 4;and pharmaceutically acceptable salts thereof.

Preferred compounds of Formula I as defined above include those where Ris substituted or unsubstituted carbocyclic aryl, particularlysubstituted or unsubstituted phenyl, naphthyl and acenaphthyl.

Substituted and unsubstiruted phenyl and naphthyl are particularlypreferred R group of compounds of Formula I, such as compounds of thefollowing Formulae Ia and Iaa: ##STR11## wherein for each of Formulae Iaand Iaa each R" is independently hydrogen, halogen, hydroxyl, azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;

p is an integer of 0 (where the phenyl ring is fully hydrogensubstituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;

s is an integer of from 0 to 7, and more preferably is 0 (where thenaphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;

R¹, R², R³, X, m and n are each the same as defmed above for Formula I;and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of Formula Ia include those where p is1 or greater, e.g. compounds that are substituted at the ortho, metaand/or para phenyl ring positions by R" group(s) other than hydrogen, or2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or2,4,5-phenyl ring substituted by R" groups other than hydrogen(s) suchas halogen, substituted or unsubstituted alkyl having 1 to about 6carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6carbon atoms, or substituted or unsubstituted alkvlthio having 1 toabout 6 carbon atoms. It is of course understood that where a phenyl ornapthyl group of Formulae Ia or Iaa is not substituted by an R" group,the ring position is hydrogen-substituted. While as shown by the abovestructure Formula Iaa includes compounds that have either a 1-naphthylor 2-naphthyl amino (--N(R¹)--) substituent, compounds having a1-naphthyl group are generally more preferred. Compounds of Formula Iaathat have a non-hydrogen R" substituent at the 4-naphthyl position arealso particularly preferred.

Compounds of Formula I may suitably contain one or more indolinyl (orderivative) ring substituents, i.e. the sum of the values of m and n ofFormula I is one or more. It is understood that references herein to"derivatives" of indolinyl compounds of Formula I refer to thosecompounds where the group X is other than substituted or unsubstitutedmethylene.

Generally preferred compounds of Formula I that include indolinyl (orderivative) substituents contain no more than one or two non-hydrogen R²substituents, such as compounds that contain 0 (i.e. ring position 2 is--CH₂ --) or 1 (i.e. ring position 2 is --CH₂ --) non-hydrogen R²substituents. Similarly, generally preferred compounds of Formula I'that include indolinyl ring substitutents contain no more than two orthree non-hydrogen R² substitutents, such as compounds that contain 0(i.e. each of ring positions 2 and 3 is --CH₂ --) or 1 (i.e. oneindolinyl ring position is --CH₂ -- and the other is --CH(R²)--)non-hydrogen R² substituents.

Generally preferred compounds of Formula I also include those thatcontain 0 (ring positions 4-7 each hydrogen substituted), and 1 or 2 R³ring substituents.

Preferred compounds of Formula I also include those compounds that areunsubstituted on the ring (each m and n as defined above for Formula Iis 0), i.e. compounds of the following Formula Ib: ##STR12## wherein thegroups R, R¹ and X are the same as defined above for Formula I; andpharmaceutically salts thereof. The above noted preferred R and R¹groups of Formula I are also preferred groups of compounds of FormulaIb.

In another aspect, compounds of Formula I" are provided, which isdefined the same as Formula I above, but where X is sulfinyl (i.e.--S(O)--) or sulfonyl (i.e. --S(O₂)--). Preferred substitutents ofcompounds of Formula I as noted herein are also preferred substituentsfor corresponding positions for compounds of Formula I".

Preferred compounds of Formula II include those where R is substitutedor unsubstituted carbocyclic aryl such as substituted or unsubstitutedphenyl, naphthyl or acenaphthyl, particularly substituted orunsubstituted phenyl or naphthyl, i.e. compounds of the followingFormulae IIa and IIaa: ##STR13## wherein for each of Formulae IIa andIIaa each R" is independently hydrogen, halogen, hydroxyl, azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;

p is an integer of 0 (where the phenyl ring is fully hydrogensubstituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;

s is an integer of from 0 to 7, and more preferably is 0 (i.e. where thenaphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;

R¹, R², R³, X, m and n are each the same as defined above for FormulaII; and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of Formula Ha include those where p is1 or greater, e.g. compounds that are substituted at the ortho, metaand/or para phenyl ring positions by R" group(s) other than hydrogen, or2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or2,4,5-phenyl ring substituted by non-hydrogen R" groups such as halogen,substituted or unsubstiruted alkyl having 1 to about 6 carbon atoms,substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, orsubstituted or unsubstituted alkylthio having 1 to about 6 carbon atoms.It is of course understood that where a phenyl or napthyl group ofFormulae IIa or IIaa is not substituted by an R" group, the ringposition is hydrogen-substituted. While as shown by the above structureFormula IIaa includes compounds that have either a 1-naphthyl or2-naphthyl amino (--N(R¹)--) substiruent, compounds having a 1-naphthylgroup are generally more preferred. Compounds of Formula IIaa that havea non-hydrogen R" substituent at the 4-naphthyl position are alsoparticularly preferred.

Compounds of Formula II may suitably contain one or moretetrahydroquinolinyl (or derivative thereof) ring substituents, i.e. thesum of the values of m and n of Formula II is one or more. It isunderstood that references herein to "derivatives" oftetrahydroquinolinyl compounds of Formula II refer to those compoundswhere the group X is other than substituted or unsubstituted methylene.

Generally preferred compounds of Formula II that includetetrahydroquinolinyl (or derivative thereof) ring substituents containno more than about three non-hydrogen R² substituents, includingcompounds that contain 0 (i.e. each of tetrahydroquinolinyl ringpositions 2, 3 and 4 is --CH₂ --) or 1 (i.e. two ring positions is --CH₂-- and the other is --CH(R¹)--) R² substituents. Generally preferredcompounds also include those that contain 0 (ring positions 5-8 eachhydrogen substituted), 1 or 2 non-hydrogen R³ ring substituents.

Preferred compounds of Formula II also include those that areunsubstituted on the tetrahydroquinolinyl (or derivative thereof) ring,i.e. m and n or Formula II are each 0, particularly compounds of thefollowing Formula IIb: ##STR14## where R and R¹ are the same as definedabove for Formula II; and pharmaceutically acceptable salts thereof. Theabove noted preferred R and R¹ groups of Formula II are also preferredgroups of compounds of Formula IIb.

In another aspect, compounds of Formula II" are provided, which isdefined the same as Formula II above, but where X is sulfinyl (i.e.--S(O)--) or sulfonyl (i.e. --S(O₂)--). Preferred substitutents ofcompounds of Formula II as noted herein are also preferred substituentsfor corresponding positions for compounds of Formula II".

Preferred compounds of Formula III include those where R is substitutedor unsubstituted carbocyclic aryl such as substituted or unsubstitutedphenyl, naphthyl or acenaphthyl, particularly substituted orunsubstituted phenyl or naphthyl, i.e. compounds of the followingFormulae IIIa and IIIaa: ##STR15## wherein for each of Formulae IIIa andIIIaa each R" is independently hydrogen, halogen, hydroxyl. azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted allynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfmyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;

p is an integer of 0 (where the phenyl ring is fully hydrogensubstituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;

s is an integer of from 0 to 7, and more preferably is 0 (i.e. where thenaphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;

R¹, R², R³, m and n are each the same as defined above for Formula III;and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of Formula IIIa include those where pis 1 or greater, e.g. compounds that are substituted at the ortho, metaand/or para phenyl ring positions by R" group(s) other than hydrogen, or2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or2,4,5-phenyl ring substituted by non-hydrogen R" groups such as halogen,substituted or unsubstitted alkyl having 1 to about 6 carbon atoms,substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, orsubstituted or unsubstituted alkylthio having 1 to about 6 carbon atoms.It is of course understood that where a phenyl or napthyl group ofFormulae IIIa or IIIaa is not substituted by an R" group, the ringposition is hydrogen-substituted. While as shown by the above structureFormula ffaa includes compounds that have either a 1-naphthyl or2-naphthyl amino (--N(R¹)--) substituent, compounds having a 1-naphthylgroup are generally more preferred. Compounds of Formula IIIaa that havea non-hydrogen R" substituent at the 4-naphthyl position are alsoparticularly preferred.

Compounds of Formula III may suitably contain one or moretetrahydroisoquinolinyl ring substituents, i.e. the sum of the values ofm and n of Formula III is one or more.

Generally preferred compounds of Formula III that includetetrahydroisoquinolinyl ring substituents contain no more than aboutthree non-hydrogen R² substituents, including compounds that contain 0(i.e. each of tetrahydroisoquinolinyl ring positions 1, 3 and 4 is --CH₂--) or 1 (i.e. two ring positions are --CH₂ -- and the other is--CH(²)--) non-hydrogen R² substituents. Generally preferred compoundsalso include those that contain 0 (ring positions 5-8 each hydrogensubstituted), 1 or 2 non-hydrogen R³ ring substituents.

Preferred compounds of Formula III also include those that areunsubstituted on the tetrahydroisoquinolinyl ring, i.e. m and n orFormula III are each 0, particularly compounds of the following FormulaIIIb: ##STR16## where R and R¹ are the same as defined above for FormulaII; and pharmaceutically acceptable salts thereof. The above notedpreferred R and R¹ groups of Formula III are also preferred groups ofcompounds of Formula IIIb.

Preferred compounds of Formula IV as defined above include those where Ris substituted or unsubstituted carbocyclic aryl, particularlysubstituted or unsubstituted phenyl, naphthyl and acenaphthyl.

Substituted and unsubstituted phenyl and naphthyl are particularlypreferred R groups of compounds of Formula IV, such as compounds of thefollowing Formulae IVa and IVaa: ##STR17## wherein for each of FormulaeIVa and IVaa each R" is independently hydrogen, halogen, hydroxyl,azido, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfmyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arninoalkl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;

p is an integer of 0 (where the phenyl ring is fully hydrogensubstituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;

s is an integer of from 0 to 7, and more preferably is 0 (i.e. where thenaphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;

R¹, R², R³, m and n are each as defined above for Formula IV; andpharmaceutically acceptable salts thereof.

Preferred compounds of Formula IVa include those where p is 1 orgreater, e.g. compounds that are substituted at the ortho, meta and/orpara phenyl ring positions by R" group(s) other than hydrogen, or2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or2,4,5-phenyl ring substituted by non-hydrogen R" groups such as halogen,substituted or unsubstiruted alkyl having 1 to about 6 carbon atoms,substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, orsubstituted or unsubstituted alkylthio having 1 to about 6 carbon atoms.It is of course understood that where a phenyl or napthyl group ofFormulae IVa or IVaa is not substituted by an R" group, the ringposition is hydrogen-substituted. While as shown by the above structureFormula IVaa includes compounds that have either a 1-naphthyl or2-naphthyl amino substituent, compounds having a 1-naphthyl group aregenerally more preferred. Compounds of Formula IVaa that have anon-hydrogen R" substituent at the 4-naphthyl position are alsoparticularly preferred.

Compounds of Formula IV may suitably contain one or more benzindolinylring substituents, i.e. the sum of the values of m and n of Formula IVis one or more.

Generally preferred compounds of Formula IV that include benzindolinylring substituents contain 0 R² substituents (i.e. the 2benz[cd]indolinyl positions is --CH₂ --), or 1 non-hydrogen R²substituent.

Generally preferred compounds of Formula IV also include those thatcontain 0 (i.e. benz[cd]indolinyl ring positions 3-8 each hydrogensubstituted), 1 or 2 R³ ring substituents.

Preferred compounds of Formula IV also include those compounds that areunsubstituted on the benzindolinyl ring (each m and n as defined abovefor Formula IV is 0), i.e. compounds of the following Formula IVb:##STR18## wherein the groups R and R¹ are the same as defmed above forFormula III; and pharmaceutically salts thereof. The above notedpreferred R and R¹ groups of Formula IV are also preferred R and R¹groups of compounds of Formula IVb.

Preferred compounds of Formula V include those where R is substituted orunsubstituted carbocyclic aryl such as substituted or unsubstitutedphenyl, naphthyl or acenaphthyl, particularly substituted orunsubstituted phenyl or naphthyl, such as compounds of the followingFormulae Va and Vaa: ##STR19## wherein for each of Formulae Va and Vaaeach R" is independenly hydrogen, halogen, hydroxyl, azido, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkylthio, substituted orunsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl,substituted or unsubstituted arninoalkyl, substituted or unsubstitutedcarbocyclic aryl, or substituted or unsubstituted aralkyl;

p is an integer of 0 (where the phenyl ring is fully hydrogensubstituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;

s is an integer from 0 to 7, and more preferably is 0 (i.e. where thenaphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;

R¹, R², R³, R⁴, m, n and r are each as defmed above for Formula V; andpharmaceutically acceptable salts thereof.

Preferred compounds of Formula Va include those where p is 1 or greater,e.g. compounds that are substituted at the ortho and/or meta phenyl ringpositions by R" groups other than hydrogen, or 2,5-phenyl ringsubstituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ringsubstituted by R" groups other than hydrogen such as halogen,substituted or unsubstituted alkyl having 1 to about 6 carbon atoms,substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, orsubstituted or unsubstituted alkylthio. It is of course understood thatwhere a phenyl or napthyl group of Formulae Va or Vaa is not substitutedby an R" group, the ring position is hydrogen-substituted. While asshown by the above structure Formula Vaa includes compounds that haveeither a 1-naphthyl or 2-naphthyl amino substituent, compounds having a1-naphthyl group are generally more preferred. Compounds of Formula Vaathat have a non-hydrogen R" substituent at the 4-naphthyl position arealso particularly preferred.

Compounds of Formula V may suitably contain one or more5,6-dihydrophenanthridinyl ring substituents, i.e. the sum of the valuesof m and n of Formula V is one or more.

Generally preferred compounds of Formula V include those compounds thatcontain 0 (i.e. the 6-hydrophenanthridinyl ring position is --CH₂ --),or 1 (i.e. the 6-hydrophenanthridinyl ring position is --CH(R²)--)non-hydrogen R² substituents. Generally preferred compounds also includethose that contain 0 (ring positions 5-8 each hydrogen substituted), 1or 2 R³ and/or R⁴ ring substiruents.

Preferred compounds of Formula V include those that are unsubstituted onthe 5,6-dihydrophenanthridinyl ring (m, n and r each zero), particularlycompounds of the following Formula Vb: ##STR20## where R and R¹ are eachthe same as defined above for Formula V; and pharmaceutically acceptablesalts thereof. The above noted preferred R and R¹ groups of Formula Vare also preferred R and R¹ groups of compounds of Formula Vb.

Suitable halogen substituent groups of compounds of Formulae I, I', I",Ia, Iaa, Ib, II, II", IIa, IIaa, IIb, III, IIIa, IIIaa, IIIb, IV, IVa,IVaa, IVb, V, Va, Vaa, Vb, VI, VII, VIII or IX, as defined above (i.e.compounds of the invention) include F, Cl, Br and I. Alkyl groups ofcompounds Formulae I, I", II, II", III, IV, V, VI, VII, VIII or IXpreferably have from 1 to about 12 carbon atoms, more preferably 1 toabout 8 carbon atoms, still more preferably 1 to about 6 carbon atoms,even more preferably 1, 2, 3 or 4 carbon atoms. (It is understood thatreferences herein to Formulae I; I"; II; II"; III; IV; and V applyequally to compounds of Formulae I', Ia, Iaa and Ib; IIa, IIaa and IIb;IIIa, IIIaa and Ib; IVa, IVaa and IVb; Va, Vaa and Vb, respectively, asthose formulae are defined herein. Hence, suitable and preferredsubstituent groups of Formulae I, I", II, II", III, IV and V are alsosuitable and preferred substituent groups of compounds of Formulae I',Ia, Iaa, Ib, IIa, IIaa, IIb, IlIa, IIIaa, IIIb, IVa, IVaa, IVb, Va, Vaaand Vb unless otherwise indicated.) Methyl, ethyl and propyl includingisopropyl are particularly preferred alkyl groups of compounds of theinvention. As used herein, the term alkyl unless otherwise modifiedrefers to both cyclic and noncyclic groups, although of course cyclicgroups will comprise at least three carbon ring members. Preferredalkenyl and alkynyl groups of compounds of the invention have one ormore unsaturated linkages and from 2 to about 12 carbon atoms, morepreferably 2 to about 8 carbon atoms, still more preferably 2 to about 6carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. The termsalkenyl and alkynyl as used herein refer to both cyclic and noncyclicgroups, although straight or branched noncyclic groups are generallymore preferred. Preferred alkoxy groups of compounds of Formulae I, I",II, II", III, IV, V, VI, VII, VIII or IX include groups having one ormore oxygen linkages and from 1 to about 12 carbon atoms, morepreferably from 1 to about 8 carbon atoms, and still more preferably 1to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms.Preferred alkyltbio groups of compounds of Formulae I through IX (whichincludes Formulae I" and II") include those groups having one or morethioether linkages and from 1 to about 12 carbon atoms, more preferablyfrom 1 to about 8 carbon atoms, and still more preferably 1 to about 6carbon atoms. Alkylthio groups having 1, 2, 3 or 4 carbon atoms areparticularly preferred. Preferred alkylsulfinyl groups of compounds ofthe invention include those groups having one or more sulfoxide (SO)groups and from 1 to about 12 carbon atoms, more preferably from 1 toabout 8 carbon atoms, and still more preferably 1 to about 6 carbonatoms. Alkylsulfmyl groups having 1, 2, 3 or 4 carbon atoms areparticularly preferred. Preferred alkylsulfonyl groups of compounds ofthe invention include those groups having one or more sulfonyl (SO₂)groups and from 1 to about 12 carbon atoms, more preferably from 1 toabout 8 carbon atoms, and still more preferably 1 to about 6 carbonatoms. Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms areparticularly preferred. Preferred aminoalkyl groups include those groupshaving one or more primary, secondary and/or tertiary amine groups, andfrom 1 to about 12 carbon atoms, more preferably 1 to about 8 carbonatoms, still more preferably 1 to about 6 carbon atoms, even morepreferably 1, 2, 3 or 4 carbon atoms. Secondary and tertiary aminegroups are generally more preferred than primary ammire moieties.Suitable heteroaromatic groups of compounds of Formulae I, I", II, II",III, IV, V, VI, VII, VIII or IX contain one or more N, O or S atoms andinclude, e.g., coumarinyl including 8-coumarinyl, quinolinyl including8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl,thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazol.Suitable heteroalicyclic groups of compounds of Formulae I, I", II, II",III, IV, V, VI, VII, VIII or IX contain one or more N, O or S atoms andinclude, e.g., tetrahydrofurnyl, tetrahydropyranyl, piperidinyl,morpholino and pyrrolindinyl groups. Suitable carbocyclic aryl groups ofcompounds of Formulae I, I", II, II", III, IV, V, VI, VII, VIII or IXinclude single and multiple ring compounds, including multiple ringcompounds that contain separate and/or fused aryl groups. Typicalcarbocyclic aryl groups contain 1 to 3 separate or fused rings and from6 to about 18 carbon ring atoms. Specifically preferred carbocyclic arylgroups include phenyl including substituted phenyl, such as2-substituted phenyl, 3-substituted phenyl, 2,3-substituted phenyl,2,5-substituted phenyl, 2,3,5-substituted and 2,4,5-substituted phenyl,including where the phenyl substituents are selected from the same groupas defined above in Formulae I-V for R³ ; naphthyl including 1-naphthyland 2-naphthyl; biphenyl; phenanthryl; and anthracyl. Suitable aralkylgroups of compounds of Formulae I, I", II, II", III, IV, V, VI, VII,VIII or IX include single and multiple ring compounds, includingmultiple ring compounds that contain separate and/or fused aryl groups.Typical aralkyl groups contain 1 to 3 separate or fused rings and from 6to about 18 carbon ring atoms. Preferred aralkyl groups include benzyland methylenenaphthyl (--CH₂ -naphthyl).

References herein to substituted R, R¹, R², R³, R⁴, R" and X groups ofcompounds of the invention refer to the specified moiety that may besubstituted at one or more available positions by one or more suitablegroups such as, e.g., halogen such as fluoro, chloro, bromo and iodo;cyano; hydroxyl; nitro; azido; alkanoyl such as a C₁₋₆ alkanoyl groupsuch as acyl and the like; carboxamido; alkyl groups including thosegroups having 1 to about 12 carbon atoms or from 1 to about 6 carbonatoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groupsincluding groups having one or more unsaturated linkages and from 2 toabout 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups havingthose having one or more oxygen linkages and from 1 to about 12 carbonatoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthiogroups including those moieties having one or more thioether linkagesand from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms;alkylsulfihyl groups including those moieties having one or more sulfmyllinkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbonatoms; alkylsulfonyl groups including those moieties having one or moresulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about6 carbon atoms; aminoalkyl groups such as groups having one or more Natoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbonatoms; carbocylic aryl having 6 or more carbons, particularly phenyl(e.g. R being a substituted or unsubstituted biphenyl moiety); andaralkyl such as benzyl. Generally preferred substituents of substitutednitrogen and methylene X groups of compounds of Formulae I, II and VIinclude the groups from which R² is selected in Formulae I, II and VI.More typical substituents of substituted nitrogen and methylene X groupsof compounds of Formulae I, II and VI include substituted andunsubstituted alkyl, including C₁₋₄ alkyl and halo-substituted C₁₋₄alky, particularly fluoro-substituted C₁₋₄ alkyl such astrifluoromethyl, and in the case of a substituted methylene group,halogen and alkylthio.

It should be understood that alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl and arinoalkyl substituent groups described above includegroups where a hetero atom is directly bonded to a ring system, such asa carbocyclic aryl group or a heterocyclic group, as well as groupswhere a hetero atom of the group is spaced from such ring system by analkylene linkage, e.g. of 1 to about 4 carbon atoms.

Preferred carbocyclic ring substituents of compounds of Formulae I, I",II, II", III, IV, V, VI, VII, VIII or IX (including substituents of thegroup R where R is a carbocyclic ring such as phenyl or naphthyl, i.e.compounds of Formula Ia, Iaa, IIa, IIaa, IIIa, IIIaa, IVa, IVaa, Va andVaa where p or s≧1 and R" is other than hydrogen) include halogen,particularly F, Cl and Br; hydroxyl; azido; substituted or unsubstitutedalkyl having 1 to about 6 carbons such as methyl, ethyl, propyl andbutyl, and including halogenated alkyl, particularly fluoro-alkyl having1 to about 6 carbon atoms; substituted and unsubstituted alkoxy having 1to about 6 carbons and including halogenated alkoxy, particularlyfluoro-alkoxy having 1 to about 6 carbon atoms; substituted andunsubstituted alkylthio having 1 to about 6 carbons; substituted andunsubstituted alkylsulfinyl having 1 to about 6 carbons; substituted andunsubstituted alkylsulfonyl having 1 to about 6 carbons; and carbocylicaryl, particularly phenyl to provide a substituted phenyl R group thatis bi-phenyl. Typically preferred phenyl ring substituents have 1 to 4carbon atoms with methyl, ethyl, propyl including isopropyl and butylincluding sec-butyl being particularly preferred. Halogen-substitutedalkyl and alkoxy groups are also particularly preferred includingfluoroalkyl having 1, 2, 3 or 4 carbon atoms such as trifluoromethyl andfluoro-substituted alkoxy having 1, 2, 3 or 4 carbon atoms such astrifluoromethoxy (--OCF₃). Methylthio (--SCH₃) and ethylthio (--SCH₂CH₃) are also particularly preferred phenyl ring substituents. Preferredalkylsulfinyl ring substituents of carbocyclic aryl groups of compoundsof the invention typically have one or more sulfoxide groups, moretypically, one or two sulfoxide groups and from 1 to about 8 carbonatoms, more preferably 1 to about 6 carbon atoms, even more preferably 1to about 3 carbon atoms. Methylsulfinyl (--S(O)CH₃) and ethylsulfinyl(--S(O)CH₂ CH₃) are particularly preferred R², R³ and R⁴ alkylsulfinylring substituents as well as preferred ring substituents of asubstituted carbocyclic R group. In particular, methylsulfinylphenyl andethylsulfinylphenyl are preferred R groups. Preferred substitutedalkylsulfinyl substituents include haloalkylsulfinyl groups that containone or more F, Cl, Br or I atoms, preferably one or more F atoms, andpreferably 1 to about 3 carbon atoms, more preferably one or two carbonatoms. Specifically preferred groups include fluoromethylsulfinyl,particularly trifluoromethylsulfinyl (--S(O)CF₃), andfluoroethylsulfinyl such as 2-trifluoroethylsulfinyl (--S(O)CH₂ CF₃) andpentafluoroethylsulfinyl (--S(O)CF₂ CF₃). Preferred alkylsulfonyl ringsubstituents of carbocyclic aryl group compounds of the invention haveone or more sulfono (SO₂) groups, more typically one sulfono group, andfrom 1 to about 8 carbon atoms, still more preferably 1 to about 6carbon atoms, even more preferably 1 to about 3 carbon atoms.Methylsulfonyl (--S(O)₂ CH₃) and ethylsulfonyl (--S(O)₂ CH₂ CH₃) areparticularly preferred sulfonoalkyl ring substituents. Preferredsubstituted allylsulfonyl substituents include haloalkylsulfonyl groupsthat contain one or more F, Cl, Br or I atoms, preferably one or more Fatoms, and preferably 1 to about 3 carbon atoms, more preferably one ortwo carbon atoms. Specifically preferred groups includefluoromethylsulfonyl, particularly trifluoromethylsulfonyl (--S(O)₂CF₃), and fluoroethylsulfonyl such as 2-trifluoroethylsulfonyl (--S(O)₂CH₂ CF₃) and pentafluoroethylsulfonyl (--S(O)₂ CF₂ CF₃).

Without wishing to be bound by theory, compounds of the invention thatcontain an alkylsulfinyl and/or alkylsulfonyl group, may be, in effect,"pro-drugs" wherein after administration of the compound to a subjectthe sulfinyl or sulfonyl group(s) are metabolized (reduced) in vivo tothe corresponding sulfide moiety.

Specifically preferred compounds of Formula I include the following:

N-(4-benzyloxyphenyl)-1-indolinylcarboxiridamide;

N-(4-methoxynaphthyl)-1-indolinylcarboximidarnide;

N-(1-naphthyl)-1-indolinylcarboximidarnide;

N-(3 ,4-dimethoxynaphthyl)-1-indolinylcarboximidamide;

N-(3,4dichlorophenyl)-1-indolinylcarboximidamide;

N-(1-naphthyl)-1-(7-ethyl)-indolinylcarboximidamide;

N-(2-naphthyl)-1-(7-ethyl)-indolinylcarboximidamide;

N-(4-sec-butylphenyl)-1-indolinylcarboximidamide;

N-(2,3-dichlorophenyl)-1-indolinylcarboximidamide;

N-(2,3-dirnethylphenyl)-1-indolinylcarboximidamide;

N-(5,6,7,8-tetrahydro-1-naphthyl)-1-indolinylcarboximidamide;

N-(2-biphenyl)-1-indolinylcarboximidamide;

N-(1-naphthyl)-N-methyl-1-indolinylcarboximidamide;

N-(2-naphthyl)-1-indolinylcarboximidamide;

N-phenyl-1-indolinylcarboximidarnide;

N-(2-chlorophenyl)-1-indolinylcarboximidamide;

N-(2-methylphenyl)-1-indolinylcarboxinidamide;

N-(3-methylphenyl)-1-indolinylcarboximidamide;

N-(2,5-dimethylphenyl)-1-indolinylcarboximidamide;

N-(2,5-dibromophenyl)-1-indolinylcarboximidamide;

N-(2,5-dichlorophenyl)-1-indolinylcarboximidamide;

N-(5-acenaphthyl)-1-(5-methoxy)-indolinylcarboximidamide;

N-(5-acenaphthyl)-1-(5-bromo)-indolinylcarboximidamide;

N-(2,3-dimethoxyphenyl)-1-indolinylcarboximidarnide;

and pharmaceutically acceptable salts of said compounds.

N-(1-naphthyl)-1-indolinylcarboximidamide and pharmaceuticallyacceptable salts thereof are particularly preferred compounds of FormulaI.

Additional preferred compounds of Formula I include the following wherethe compound is structurally depicted above the chemical name thereof,and pharmaceutically acceptable salts of these depicted compounds.##STR21##

Specifically preferred compounds of Formula II include the following:

N-(1-naphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(1-naphthyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboxinriidamide;

N-(1-naphthyl)-1-(7-methyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(2,5-dibromophenyl)-1-(7-trifluorometihyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(1-naphthyl)-1-(2-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboxirnidamide;

N-(4-benzyloxyphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(4-methoxynaphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(3,4-dichlorophenyl)-1-(1,2,3,4-terrahydroquinolinyl)carboxirnidamide;

N-(5-acdnaphthyl)-1-(5-methoxy)-(1,2,3,4-tetrahydroquinolinyl)carboxinidaraide;

N-(5-acenaphthyl)-1-(5-bmromto)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(5-naphthyl)-1-(7-ethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(4-sec-burylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(2,3-dichlorophenyl)-1-(1,2,3,4-terrahydroquinolinyl)carboximidamide;

N-(2 3-dimethylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(2-biphenyl)-1-(1,2,3,4-retrahydroquinolinyl)carboximidamide;

N-(3-biphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximnidamide;

N-(1-naphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(2-ethylphenyl)-1-(1,2,3,4-tetrthydroquinotinyl)carboximidamide;

N-(3-ethylphenyl)-1-(1,2,3,4-rerahydroquinolinyl)carboximidarnide;

N-(2,5-dimethylphenyl)-1-(1,2,3,4-cetrahydroquinolinyl)carboximidamide;

N-(2-chloro-5-ethylphenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(2,5-dibromophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(2,5-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(3-methylthiophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

N-(2,3-difluorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;

and pharmaceutically acceptable salts of said compounds.

N-(2,5-dibromophenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide and pharmaceutically acceptable salts thereof areparticularly preferred compounds of Formula II, i.e. the compound of thefollowing structure and pharmaceutically acceptable salts thereof:##STR22##

Additional preferred compounds of Formulae II and II' include thefollowing where the compound is structurally depicted above the chemicalname thereof, and pharmaceutically acceptable salts of these depictedcompounds. ##STR23##

Specifically preferred compounds of Formula III include dhe following:

N-(1-naphthyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(1-naphthyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(1-naphthyl)-1-(7-methyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(2,5-dibromophenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(1-naphthyl)-1-(2-trifluoromethyl)-(1,2,3,4tetrahydroisoquinolinyl)carboximidamide;

N-(4-benzyloxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(4-methoxynaphthyl)-1-(1,2,3,4-terrahydroisoquinolinyl)carboximidamide;

N-(3,4-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(5-acenaphthyl)-1-(5-methoxy)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(5-acenaphthyl)-1-(5-bromo)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(1-naphthyl)-1-(7-ethyl)-(1,2,3,4-terrahydroisoquinolinyl)carboximidamide;

N-(4-sec-butylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximldamide;

N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(2,3-dimethylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(2-biphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(3-biphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(1-naphthyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(2-ethylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboxirnidamide;

N-(3-ethylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(2,5-dimethylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(2-chloro-5-ethylphenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(2,5-dibromophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(2,5-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(3-methylthiophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

N-(2,3-difluorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;

and pharmaceutically acceptable salts of said compounds.

Specifically preferred compounds of Formula IV include the following:

N-(3-biphenyl)-1-(benz[cd]indolinyl)carboximidamide;

N-(1-naphthyl)-1-(benz[cd]indolinyl)carboximidamide;

N-(2-methylphenyl)-1-(benz[cd]indolinyl)carboximidamide;

N-(2,3-dimethylphenyl)-1-(benz[cd]indolinyl)carboximidamide;

N-(2,5-dimethylphenyl)-1-(benz[cd]indolinyl)carboximidamide;

N-(4-benzyloxyphenyl)-1-(benz[cd]indolinyl)carboximnidamide;

N-(4-methoxynaphthyl)-1-(benz[cd]indolinyl)carboximidamide;

N-(3,4-dichlorophenyl)-1-(benz[cd]indolinyl)carboximidamide;

N-(5-acenaphthyl)-1-(5-methoxy)-1-(benz[cd]indolinyl)carboximidamide;

N-(5-acenaphthyl)-1-(5-bromo)-(benz[cd]indolinyl)carboximidamide;

N-(1-naphthyl)-1-(7-ethyl)-(benz[cd]indolinyl)carboximidamnide;

N-(4-sec-butylphenyl)-1-(benz[cd]indolinyl)carboximidamide;

N-(2,3-dichlorophenyl)-1-(benz[cd]indolinyl)carboximidarnide;

N-(3-methylphenvl)-1-(benz[cd]indolinyl)carboximidamide;

N-(5,6,7,8-cetrahydro-1-naphthyl)-1-(benz[cd]indolinyl)carboximidarnide;

N-(2-biphenyl)-1-(benz[cd]indolinyl)carbo.imidamide;

N-(1-naphthyl)-1-(7-trifluoromethyl)-(benz[cd]indoiinyl)carboximidamide;

N-(3-ethylphenyl)-1-(benz [cd]indolinyl)carboximidamide;

N-(2,5-dibromophenyl)-1-Cbenz[cd]indolinyl)carboximidaraide;

N-(2,5-dichlorophenyl)-1-(benz[cd]indolinyl)carboximidamide;

and pharmaceutically acceptable salts of said compounds. ##STR24##

Specifically preferred compounds of Formula V include the following:

N-(1-naphthyl)-1-(5,6-dihydrophenanthridinyl)carboxuizdarnide;

N-(4benzyloxyphenyl)-1-(5,6-dihydrophenanthridinyl)carboimidamide;

N-(4methoxynaphthyl)-1-(5,6-dihydrophenanthridinyl)carboximidamride;

N-(3,4-dichlorophenyl)-1-(5,6-dihydrophenanthridinyl)carboxirndarnide;

N-(5-acenaphthyl)-1-(5-methoxy)-1-(5,6-dihydrophenanthridinyl)carboxiidamnide;

N-(5-acenaphchyl)-1-(5-bromo)-(5,6-diydrophenanthridinyl)carboximidamide;

N-(1-naphthyl)-1-(7-erhyl)-(5,6-dihydrocphenanthridinyl)carboximidamide;

N-(4-sec-butylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;

N-(2,3-dichlorophenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;

N-(2,3-dimethylphenyl)-1-(5,6-dihydrophenantlridinyl)carboxinidaniide;

N-(5,6,7,8-terrahydro-1-naphthyl)-1-(5,6-dihydrophenanthridinyl)carboximidarnide;

N-(2-biphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;

N-(3-biphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidarnide;

N-(1-naphthyl)-1-(5,6-dihydrophenanthridinyl)carbo,ximidamide;

N-(1-naphthyl)-1-(7-trifluoromethyl)-(5,6-dihydrophenanthridinyl)carboximidamide;

N-(2-methylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;

N-(3-ethylphenyl)-1-(5,6-dihydropheanthridinyl)carboximidamide;

N-(2,5-dimethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidarnide;

N-(2-ethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboxirnidamide;

and pharmaceutically acceptable salts of said compounds.

Specificallv preferred compounds of Formula VI include the followingwhere the where the compound is structurally depicted above thechernical name thereof, and pharmaceutically acceptable salts of thesedepicted compounds: ##STR25##

Specifically preferred compounds of Formula VII include the followingwhere the where the compound is structurally depicted above the chemicalname thereof, and pharmaceutically acceptable salts of these depictedcompounds: ##STR26##

Specifically preferred compounds of Formulae VIII and IX include thefollowing where the where the compound is structurally depicted abovethe chemical name thereof, and pharmaceutically acceptable salts ofthese depicted compounds: ##STR27##

Excluded from certain aspects of the invention areN-(alkylphenyl)-1-indolinylcarboximidamide compounds (i.e. compounds ofFormula I where X is CH₂ and R is alkyl-substituted phenyl, particularlywhere R¹ is H), specificallyN-(mono-alkylphenyl)-1-indolinylcarboximidamide such asN-(m-ethylphenyl)-1-indolinyl carboximidarnide; as well as compounds ofthe invention where R is acenaphthyl, particularly where R isunsubstituted acenaphthyl and/or ring substituents R² and R³ are eachonly hydrogen, and/or where X is CH₂ in the case of Formulae I and II,and/or one of R and R¹ is hydrogen; as well as compounds of Formula IIIwhere R or R¹ is aralkyl, particularly where ring substituents R² and R³are each only hydrogen, and/or R and R¹ are each other than hydrogen.

Compounds of the invention can be prepared by the reaction of a suitableprecursor compound, e.g. indolinyl (or derivative thereof) compound,1,2,3,4-tetrahydroquinolinyl (or derivative thereof) compound,1,2,3,4-tetrahydroisoquinolinyl compound, benz[cd]indolinyl compound,5,6-dihydrophenandhridinyl compound,2,3,4,5-tetrahydro-[1,5]-benzothiazepine compounds (or derviativethereof, e.g. where X is other atom), 2a,3,4,5-tetrabenz[cd]indolinecompound, 5,6,11,12-tetrahydrodibentb,flazocine compound, etc.(depending on whether a compound of Formulae I, I", II, II", III, IV, V,VI, VII, VIII or IX respectively, is being prepared) with a preformedalkyl or aryl cyanamide (see S. R. Safer, et al., J. Org. Chem., 13:924(1948)) or the corresponding N-substituted alkyl or aryl cyanamide.Typically, a salt of the amine (e.g. an HCl salt) is reacted with thecyanamide.

More particularly, compounds the invention can be suitably prepared byreaction of an appropriate indolinyl (or derivative thereof) salt (toprepare compounds of Formulae I, I', I", Ia, Iaa or Ib),1,2,3,4-tetrahydroquinolinyl (or derivative thereof) salt (to preparecompounds of Formulae II, II", IIa, IIaa or Ib),1,2,3,4-tetrahydroisoquinolinyl salt (to prepare compounds of FormulaeIII, IIIa, IIIaa or IIIb), benz[cd]indolinyl salt (to prepare compoundsof Formulae IV, IVa, IVaa or IVb), or 5,6-dihydrophenanthridinyl salt(to prepare compounds of Formulae V, Va, Vaa or Vb) or other appropriatesalt such as salts of above mentioned precursor compounds (to formcompounds of Formulae VI-IX) with a substituted cyanamide in a suitablesolvent such as toluene, chlorobenzene or the like under an inertatmosphere such as argon or nitrogen as exemplified in the Scheme below.The reaction solution is then heated e.g. from about 110° to 120° C. for2 to about 16 hours until reaction completion, e.g. as indicated by thinlayer chromatography. The reaction solution is then cooled to roomtemperature, and the solvent is then removed under reduced pressure toprovide the desired compound of the invention. The crude product thencan be purified by recrystallization and/or column chromatography, e.g.by elution one or more times on silica gel (e.g., 60-200 mesh, 50× w/w)with suitable solvents. See Example 2 which follows for exemplaryconditions.

The indolinyl (or derivative thereof), 1,2,3,4-tetrahydroquinoline (orderivative thereof), 1,2,3,4-tetrahydroisoquinoline, benz[cd]indolinylor 5,6-dihydrophenanthridinyl ot other presursor such as those mentionedabove (for Formulae VI-IX) and cyanamide reagents with appropriatesubstituents are commercially available or can be readily prepared byknown procedures. For example, the cyanamide starting material can besynthesized from the correspondingly substituted amine by treatment withcyanogen bromide (BRCN) in a suitable solvent such as dry ethyl ether ortoluene at reduced temperatures (e.g. 0° C.) or room temperature. Asexemplified in the Scheme below, the amine to be reacted with cyanogenbromide is substituted with the R moiety as defined above for FormulaeI, I", II, II", III, IV, V, VI, VII, VIII or IX (in the Scheme, that Rmoiety is exemplified as phenyl which may be ring-substituted by groupsR₁ and R₂). Thus, various R groups of compounds of Formula I through IX(Which includes Formulae I" and II") can be provided by use of suitablesubstituted amies that are reacted with BrCN, such as e.g. substitutedand unsubstiruted anilines as shown in the Scheme, substituted andunsubstituted 1-naphthylarine, 2-naphthylamine, acenaphthylamine, etc.R¹ groups other than hydrogen of compounds of Formulae I through IX canbe readily provided by reaction of a substituted cyanamide with asuitable nucleophile such as a halide reagent (e.g., a substituted orunsubstiruted alkyl or alklnyl iodide or bromide). Thus, as exemplifiedin the Scheme below, the aryl cyanamide is reacted with NaH in a solventof tetrahydrofuran and reacted with the iodide reagent R¹ -I, such assubstituted or unsubstituted methyl, ethyl, propyl, butyl, etc. iodide,an alkenyl iodide, etc. Also, compounds of the invention having an R¹group of methyl can be prepared by reaction of a mono-substituted amine(e.g., an aniline, naphthylamine or acenaphthylamine) with formic acidfollowed by treatment with lithium aluminum hydride to provide thecorresponding methyl-substituted cyanamide (e.g., C₆ H₅ N(CH₃)CN fromunsubstituted aniline). Alkylsulfmyl-substituted oralkylsulfonyl-substituted reagents, that can provide correspondinglysubstituted compounds of the invention as described above, can beprovided by oxidation (e.g., H₂ O₂) of alkylthio-substituted reagents.See for instance Example 46 which follows.

While the Scheme depicts preparation of compounds of Formula I, the sameprocedures can be employed to prepare compounds of Formulae I', II, II",III, IV, V, VI, VII, VIII or IX by use of a 1,2,3,4-tetrahydroquinolinyl(or derivative thereof) salt, 1,2,3,4-tetrahydroisoquinolinyl salt,benz[cd]indolinyl salt or 5,6-dihydrophenanthridinyl salt or othercorresponding salt for compounds of Formulae VI through IX,respectively, in place of the indolinyl salt shown in the Scheme.##STR28##

Compounds of Formula II where R and R¹ are each hydrogen can be preparedby reaction of 1,2,3,4-tetrahydroquinoline compound with cyanamnide. R²substituents can be provided by reaction of a substituted orunsubstituted quinoline compound with a Grignard reagent followed byhydrogenation to provide the substituted 1,2,3,4-tetrahydroquinolinecompound. See Example 3 which follows for an exemplary procedure. Seealso Examples 41 and 42 which follow. Compounds of Formulae I", II" andVI where X is --S(O)-- or --S(O)₂ -- can be prepared by oxidation (e.g.with H₂ O₂ and/or with sodium periodate) of the corresponding preformedcompounds where the ring member X is --S--. See for instance Example 47which follows.

The amine starting materials are commercially available andior can bereadily prepared. For example, benz[cd]indoline and5,6-dihydrophenanthridine reagents can be prepared treatment of abenz[cd]indo-2(1H)-one compound or 5,6-dihydrophenanthridinone compoundwith a base such as diborane in a suitable solvent such astetrahydrofuran. See Example 1 which follows for exemplary conditions.Chiral compounds of the invention may be used as optically enriched orracemic mixtures. An optically enriched mixture contains substantiallymore (e.g. about 60%, 70%, 80% or 90% or more) of one enantiomer ordiastereoisomer than the other stereoisomers. Optically enrichedmixtures can be obtained by known procedures, e.g., columnchromatography using an optically active binding material or formationof a salt using an optically active material, particularly an opticallyactive acid. Particularly preferred optically enriched mixtures includesulfinyl-containing compound of the invention, e.g. compounds ofFormulae I", II" or VI where X is --S(O)--, or compounds having havingan alkylsulfmyl or other sulfinyl substituent. Such optically activemxtures of sulfinyl-containing compounds can be readily prepared, e.g.by column chromatography using an optically active binding material.

As discussed above, the present invention includes methods for treatingpreventing certain neurological disorders, including the consequences ofstroke, heart attack and traumatic head or brain injury, epilepsy orneurodegenerative diseases comprising the administration of an effectiveamount of one or more compounds of the invention to a subject includinga mammal, particularly a human, in need of such treatment. Inparticular, the invention provides methods for treatment and/orprophylaxis of nerve cell death (degeneration) resulting e.g. fromhypoxia, hypoglycemia, brain or spinal cord ischemia, brain or spinalcord trauma, stroke, heart attack or drowning. Typical candidates fortreatment include e.g. heart attack, stroke and/or persons sufferingfrom cardiac arrest neurological deficits, brain or spinal cord injurypatients, patients undergoing major surgery such as heart surgery wherebrain ischemia is a potential complication and patients such as diverssuffering from decompression sickness due to gas emboli in the bloodstream. Candidates for treatment also will include those patientsundergoing a surgical procedure involving extra-corporal circulationsuch as e.g. a bypass procedure.

The invention in particular provides methods for treatment whichcomprise administration of one or more compounds of the invention to apatient that is undergoing surgery or other procedure where brain orspinal cord ischemia is a potential risk. For example, carotidendarterectomy is a surgical procedure employed to correctatherosclerosis of the carotid arteries. Major risks associated with theprocedure include intraoperative embolization and the danger ofhypertension in the brain following increased cerebral blood flow, whichmay result in aneurism or hemorrhage. Thus, an effective amount of oneor more compounds of the present invention could be administeredpre-operatively or peri-operatively to reduce such risks associated withcarotid endarterectomy, or other post-surgical neuorological deficits.

The invention further includes methods for prophylaxis againstneurological deficits resulting from e.g. coronary artery bypass graftsurgery and aortic valve replacement surgery, or other procedureinvolving extra-corporal circulation. Those methods will compriseadministering to a patient undergoing such surgical procedures aneffective amount of one or more compounds of the invention, typicallyeither pre-operatively or peri-operatively.

The invention also provides methods for prophylaxis and treatmentagainst neurological injury for patients undergoing myocardialinfarction, a procedure that can result in ischemic insult to thepatient. Such methods will comprise administering to a patientundergoing such surgical procedure an effective amount of one or morecompounds of the invention, typically either pre-operatively orperi-operatively.

Also provided are methods for treating or preventing neuropathic painsuch as may experienced by cancer patients, persons having diabetes,amputees and other persons who may experience neuropathic pain. Thesemethods for treatment comprise administration of an effective amount ofone or more compounds of the invention to a patient in need of suchtreatment.

The invention also provides methods for treatment and prophylaxisagainst retinal ischemia or degeneration and resulting visual loss. Forexample, a compound of the invention can be administered parenterally orby other procedure as described herein to a subject a suffering from orsusceptible to ischemic insult that may adversely affect retinalfunction, e.g., significantly elevated intraocular pressures, diseasessuch as retinal artery or vein occlusion, diabetes or other ischemicocular-related diseases. Post-ischemic administration also may limitretinal damage. The invention also includes methods for treating andprophylaxis against decreased blood flow or nutrient supply to retinaltissue or optic nerve, or treatment or prophylaxis against retinaltrauma or optic nerve injury. Subjects for treatment according to suchtherapeutic methods of the invention may be suffering or susceptible toretinal ischemia that is associated with atherosclerosis, venouscapillary insufficiency, obstructive arterial or venous retinopthies,senile macular degeneration, cycstoid macular edema or glaucoma, or theretinal ischemia may be associated with a tumor or injury to the mammal.Intravitreal injection of a compound of the invention also may be apreferred administration route to provide more direct treatment to theischemic retina.

The invention also provides methods for treatment of a subject sufferingfrom shingles as well as treatment of a person suffering from orsusceptible to migraines, particularly to alleviate the pain anddiscomfort associated with those disorders. These methods compriseadministration of an effective amount of one or more compounds of theinvention to a patient in need of treatment.

The invention further provides a method of treating Korsakoff's disease,a chronic alcoholism-induced condition, comprising administering to asubject including a mammal, particularly a human, one or more compoundsof the invention in an amount effective to treat the disease. Compoundsof the invention are anticipated to have utility for the attenuation ofcell loss, hemorrhages and/or amino acid changes associated withKorsakoff's disease.

As discussed above, the invention also includes methods for treating aperson suffering from or susceptible to cerebral palsy, emesis, narcoticwithdrawal symptoms and age-dependent dementia, comprising administeringto a subject including a mammal, particularly a human, one or morecompounds of the invention in an amount effective to treat thecondition.

As discussed above, preferred compounds of the invention in a standardanticonvulsant in vivo audiogenic test, such as the audiogenic mouseassay of Example 48 which follows, where DBA/2 mice about 20-23 days oldare injected intraperitoneally with a test compound 30 minutes prior tobeing placed in a bell jar with exposure to auditory stimulus of 12 KHzsine wave at 110-120 db. References herein in vivo "audiogenic assay"are intended to refer to that protocol. Generally preferred compoundsexhibit 20% or more inhibition (relative to subjects treated withvehicle control only) at a dose of 20 mg/kg, more preferably about 50%or more or 70% or more inhibition at a dose of 20 mg/kg in such an invivo audiogenic assay. As discussed above, activity in the audiogenicassay has been recognized as indicative that a test compound hasneuroprotective properties. See, e.g., M. Tricklebank et al., EuropeanJournal of Pharmacology, supra; T. Seyfried, Federation Proceedings,supra.

The invention also provides methods for determining binding activity ofcompounds of the invention as well as in vitro and in vivo bindingactivity diagnostic methods using one or more radiolabelled compounds ofthe invention, e.g., a compound of the invention that is labeled with¹²⁵ I, tritium, ³² P, ⁹⁹ Tc, or the like, preferably 125I. For instance,a compound of the invention having a phenyl or other aryl substituentthat is ring substituted with one or more ¹²⁵ I groups can beadministered to a mammal and the subject then scanned for binding of thecompound. Specifically, single photon emission computed tomography("SPECT") can be employed to detect such binding. Such an analysis ofthe mammal could e.g. aid in the diagnosis and treatment of acutecerebral ischemia. That is, a labeled compound of the invention willselectively bind to ischernic tissue of e.g. a subject's brain todifferentiate between ischemic and non-ischemic tissue and therebyassess trauma or other injury to the brain.

Accordingly, the invention includes compounds of the invention thatcontain a radiolabel such as ¹²⁵¹ I, tritium, ³² P, ⁹⁹ Tc, or the like,preferably ¹²⁵ I. Such radiolabelled compounds can be suitably preparedby procedures known in the synthesis art. For example, a compound of theinvention having an aromatic group, such as phenyl, that has a bromo orchloro ring substituent can be employed in an exchange labeling reactionto provide the corresponding compound having an ¹²⁵ I ring substituent.

Compounds of the invention may be used in therapy in conjunction withother medicaments. For example, for treatment of a stroke victim or aperson susceptible to stroke, one or more compounds of Formulae I, II,III, IV or V, or one or compounds of Formulae I", II", VI, VU, VIII orIX, may be suitably administered together with a pharmaceutical targetedfor interaction in the blood clotting mechanism such as streptokinase,tPA, urokinase and other agents that lyse clots. Also, one or morecompounds of the invention may be administered together with agents suchas heparin and related heparin-based compounds, acenocoumarol or otherknown anticoagulants.

The compounds of this invention can be administered intranasally, orallyor by injection, e.g., intramuscular, intraperitoneal, subcutaneous orintravenous injection, or by transdermal, intraocular or enteral means.The optimal dose can be determined by conventional means. Compounds ofthe present invention are suitably administered to a subject in theprotonated and water-soluble form, e.g., as a pharmaceuticallyacceptable salt of an organic or inorganic acid, e.g., hydrochloride,sulfate, hemi-sulfate, phosphate, nitrate, acetate, oxalate, citrate,maleate, mesylate, etc.

Compounds of the invention can be employed, either alone or incombination with one or more other therapeutic agents as discussedabove, as a pharmaceutical composition in mixture with conventionalexcipient, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for parenteral, enteral or intranasalapplication which do not deleteriously react with the active compoundsand are not deleterious to the recipient thereof. Suitablepharmaceutically acceptable carriers include but are not limited towater, salt solutions, alcohol, vegetable oils, polyethylene glycols,gelatin, lactose, amylose, magnesium stearate, talc, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorings, flavorings and/oraromatic substances and the like which do not deleteriously react withthe active compounds.

For parenteral application, particularly suitable are solutions,preferably oily or aqueous solutions as well as suspensions, emulsions,or implants, including suppositories. Ampules are convenient unitdosages.

For enteral application, particularly suitable are tablets, dragees orcapsules having talc and/or carbohydrate carrier binder or the like, thecarrier preferably being lactose and/or corn starch and/or potatostarch. A syrup, elixir or the like can be used wherein a sweetenedvehicle is employed. Sustained release compositions can be formulatedincluding those wherein the active component is protected withdifferentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc.

Intravenous or parenteral administration, e.g., sub-cutaneous,intraperitoneal or intramuscular administration are preferred. Thecompounds of this invention are particularly valuable in the treatmentof mammalian subjects, e.g., humans, to provide neuroprotective therapyand/or prophylaxis. Typically, such subjects include those afflictedwith neurodegenerative diseases such as Parkinson's disease,Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer'sdisease, Down's Syndrome and Korsakoff's disease. Also suitable fortreatment are those subjects suffering from or likely to suffer fromnervous system dysfunctions resulting from, for example, epilepsy ornerve cell degeneration which is the result of hypoxia, hypoglycemia,brain or spinal chord ischemia or brain or spinal chord trauma. Asdiscussed above, typical candidates for treatment include heart attack,stroke, brain or spinal cord injury patients, patients undergoing majorsurgery where brain or spinal cord ischemia is a potential complicationand patients such as divers suffering from decompression sickness due togas emboli in the blood stream.

It will be appreciated that the actual preferred amounts of activecompounds used in a given therapy will vary according to the specificcompound being utilized, the particular compositions formulated, themode of application, the particular site of administration, etc. Optimaladministration rates for a given protocol of administration can bereadily ascertained by those skilled in the art using conventionaldosage determination tests conducted with regard to the foregoingguidelines. In general, a suitable effective dose of one or morecompounds of Formulae I, II, III, IV or V, or one or compounds ofFormulae I", II", VI, VII, VIII or IX, particularly when using the morepotent compound(s) of Formulae I, II, III, IV or V, or one or compoundsof Formulae I", II", VI, VII, VIII or IX, will be in the range of from0.01 to 100 milligrams per kilogram of bodyweight of recipient per day,preferably in the range of from 0.01 to 20 milligrams per kilogrambodyweight of recipient per day, more preferably in the range of 0.05 to4 milligrams per kilogram bodyweight of recipient per day. The desireddose is suitably administered once daily, or several sub-doses, e.g. 2to 4 sub-doses, are administered at appropriate intervals through theday, or other appropriate schedule. Such sub-doses may be administeredas unit dosage forms, e.g., containing from 0.05 to 10 milligrams ofcompound(s) of Formulae I, II, III, IV or V, or one or compounds ofFormulae I", II", VI, VII, VIII or IX, per unit dosage, preferably from0.2 to 2 milligrams per unit dosage.

Compounds of the invention also should be useful as rubber accelerators.See U.S. Pat. No. 1,411,713 for a discussion of rubber acceleratorapplications.

The entire text of all documents cited herein are incorporated byreference herein. The following non-limiting examples are illustrativeof the invention.

GENERAL COMMENTS

In the following examples, all percentages reported herein, unlessotherwise specified, are percent by weight. All temperatures areexpressed in degrees Celsius.

Melting points were determined in open capillary tubes on aThomas-Hoover apparatus and are uncorrected. Thin-layer chromatographywas performed on Baker-flex 1B2-F silica gel plates. Compounds werevisualized on TLC with 254-nM UV light or as a blue spot with bromcresolspray reagent (Sigma Chemical Co.). Preparative TLC was performed onAnaltech GF precoated silica gel (1000 μm) glass-backed plates (20×20cm). The IR, ¹ H and ¹³ C NMR spectra of all compounds were consistentwith their assigned structures. NMR spectra were recorded on VarianGemini 300 and the chemical shifts were reported in ppm (δ) relative tothe residual signal of the deuterated solvent (CDCl₃, δ 7.26; CHD₂ OD, δ3.30). Elemental analyses were performed by either GalbraithLaboratories (Knoxville, Tenn.) or MHW Laboratories (Tuscon, Ariz.).High Resolution Mass spectra (HRMS) were recorded on a Finnegan MAT 90.HPLC were performed on a C18 reverse phase column using 50:50water:acetonitrile with 0.1% TFA as a mobile phase. BrCN was obtainedfrom Aldrich Chemical Co., and was used as received. All starting amineswere obtained from commercial sources and were purified by standardprocedures before use, or they were prepared by published procedures.Chlorobenzene, ether (Et₂ O) and tetrahydrofuran (THF) were anhydrousquality solvents (Sure Seal) supplied by Aldrich. All other solventswere reagent grade. Alkyl- and arylcyanamides were prepared as describedabove and according to published procedures (e.g., PCT/US92/01050) byreaction of the amines with BrCN in ether.

EXAMPLE 1 ##STR29##

To a cooled (ice bath) solution of Benz[cd]indo-2(1H)-one (9.0 g, 53.2mmol) in tetrahydrofuran (50 ml) was added dropwise 100 ml of diborane1M in tetrahydrofuran (100 mmol) under argon. The resulting mixture wasrefluxed for 12 hours and quenched with aqueous HCl (1M) at 0-5° C. Thesolution was basified to pH 14 by adding NaOH 1N and the productextracted with chloroform. The combined organic layers were washed withbrine and dried over MgSO₄. Flash column chromatography (silica gel, 2:1hexane/dichloromethane) afforded Benz[cd]indoline (5.58 g, 67.6%). Toform the HCl salt, Benz[cd]indoline (1.0 g, 6.44 mmol) was thendissolved in a minimum amount of diethyl ether and 15 ml of 1M HCldiethyl ether solution was added. The precipitate was collected byfiltration, washed with diethyl ether and dried to affordBenz[cd]indoline HCl (1.21 g, 98%) as a white solid. ¹ H-NMR (CD₃ OD): δppm 7.90-7.55 (m, ArH, 6H), 5.16 (s, ArCH2, 2H). ##STR30##

The title compound was obtained as a white solid from6(5H)-phenanthridinone by the method described in Example 1(a) above in12% yield. ¹ H-NMR (CD₃ OD): δ ppm 8.12-7.45 (m, ArH, 6H), 4.59 (s,ArCH2, 2H).

EXAMPLE 2 Preparation of N-(1-Naphthyl)-1-indolinylcarboximidamide(Formula I: R=1-naphthyl, R¹ =hydrogen, m=n=0)

Part 1: Preparation of 1-Naphthylcyanamide

Cyanogen bromide (4.4 gm, 41.9 mmol) was added in portions to thestirred and ice-bath cooled solution of 1-aminonaphthalene (10.0 gm,69.8 mmol) in toluene (100 mL. After 0.5 hour, the cooling bath wasremoved the reaction mixture was stirred at room temperature for 12hours. The precipitate was filtered and the solid was triturated withwater (150 mL) for 0.5 hour. The resulted solid was filtered and washedwith water (4×20 mL) and the solid was dried in vacuum oven at 40° C.This material (4.6 gm) was used as such without any furtherpurification.

Part 2: Preparation of N-(1-Naphthyl)-1-indolinylcarboximidamidemesylate

A mixture of 1-naphthylcyanamide (610 mg, 3.63 inmol), indoline mesylate(663 m, 3.09 mmol) and chlorobenzene (18 ml) in a round bottom flaskwere heated to reflux on an oil bath for 4 hours. The reaction wasallowed to cool to room temperature, solvent was removed by rotavapor,and the residue was chromatographed on silica gel using a mnixture ofhexanes: ethyl acetate (2:1) followed by chloroform/methanol (10:1) aseluents. The white foam-solid obtained upon concentration of fractionswas treated with diethyl ether for overnight. White solid was filteredwashed with diethyl ether to give the title product as free base aswhite solid; mp: 151-155° C.; TLC (CHCl₃ :MeOH; 10:1); R_(f) =0.23; ¹ HNMR(CDCl₃): 8.173-8.144 (m, ArH, 1H), 7.856-7.826 (m, ArH, 2H),7.574-7.405 (m, ArH, 2H), 7.240-7.154 (m, ArH, 2H), 7.080-7.052 (m, ArH,1H), 6.952-6.927 (m, ArH, 1H), 4.208-4.152 (t, J=8.45 Hz, CH₂, 2H),3.231-3.174 (t, J=8.45 Hz, CH₂, 2H); Anal. Calcd. for C₁₉ H₁₇ N₃ 0.5H₂O; C: 77.0, H: 6.07, N: 14.18; Found C: 76.10, H: 5.78, N: 13.98.

EXAMPLE 3 Preparation of (±)2-(4-tert-butylphenyl)-6-isopropyl-1-(1,2,3,4-(tetrahydroquinolinylcarboximidamide)hydrochloride (Formula II: hydrochloride salt of R=R¹ =H, R²=2-(4-tert-butylphenyl), R³ =6-isopropyl, X=CH₂, m=n=1) ##STR31##

To a cooled (ice bath) 2M diethyl ether solution of4-tert-butylphenylmagnesium bromide (15 ml, 0.03 mol) was added dropwiseunder argon 15 ml of a tetrahydrofuran solution of 6-isopropylquinoline(5.13 g, 0.03 mol). The resulting mixture was refluxed for 5 hours,stirred at room temperature for 12 hours and quenched with water (80ml). The yellow precipitate obtained was then filtered and washed withhexane. CrystaUization in hexane:chloroform 40:1 yielded 3.7 g of pure(±)-2-(4-tert-burylphenyl)-6-isopropylquinoline (40% yield). ¹ HNMR(CDCl₃): 8.2 (m, ArH, 4H), 7.84 (m, ArH, 1H), 7.60 (m, ArH, 4H), 3.12(s, CH(Me)₂, 1H), 1.4 (s, CH(Me)₂ and C(Me)₃, 15H); Mass/Cl-NH₃ : MH⁺304. ##STR32##

2-(4-tert-butylphenyl)-6-isopropylquinoline (2.5 g, 8.2 mmol) wasdissolved in 100 ml of methanol; platinum (IV) oxide (300 mg, 1.3 mmol)was added and the suspension hydrogenated at 50 psi for 12 hours. Thecatalyst was filtered off on a bed of celite and 20 ml of 1N HCl inethyl ether was added to the filtrate which was then concentrated toyield crude(±)-2-(4tert-butylphenyl)-6-isopropyl-1,2,3,4-tetrahydroquinolinehydrochloride. Mass/Cl-NH₃ : MH⁺ 308. ##STR33##

The crude(±)-2-(4-tert-burylphenyl)-6-isopropyl-1,2,3,4-tetrahydroquinolinehydrochloride (300 mg, approximately 0.8 mmol) obtained in Part 2 aboveand cyanarnide (350 mg, 8 mmol) were dissolved in ethanol and themixture heated to reflux for 2 days. The solvent was evaporated, waterwas added and the product extracted with ethyl acetate. The crudeproduct was purified on silica gel with chloroform: methanol 9:1 aseluant. The obtgained solid was washed successively with water and ethylether to yield (±)2-(4-tert-butylphenyl)-6-isopropyl-1-(1,2,3,4-tetrahydroquinoliylcarboximidamide)hydrochloride (70 mg, 21%). ¹ H NMR(CD₃ OD): δ ppm 7.40 (m, ArH, 3H),7.20 (m, ArH, 4H), 5.30 (M, CHN, 1H), 2.90 (s, CH(Me)₂, 1H), 2.70 (m,CH₂, 2H), 1.9 (m, CH₂, 2H), 1.25 and 1.28 (s, CH(Me)₂ and C(Me)₃, 15H);Mass/Cl-NH₃ : MH⁺ 350.

EXAMPLES 4-47

By methods indicated above in Examples 1-3 and using appropriatelysubstituted reagents, the following compounds were prepared having thespecified physical characteristics.

EXAMPLE 4 N-(4-Benzyloxyphenyl)-1-indolinylcarboximidamide•mesylate(Formula I: mesylate salt of R=4-benzyloxyphenyl, R¹ =H, m=n=0)

White solid; mp: 144-145° C.; TLC (CHCl₃ :MeOH; 10:1); R_(f) =0.37; ¹ HNMR (CDCl₃): 7.391-6.858 (m, ArH, 13H), 5.000 (s, CH₂, 2H), 3.894-3.841(t, J=7.97 Hz, CH₂, 2H), 3.143-3.090 (t, J=7.97 Hz, CH₂, 2H), 2.706 (s,CH₃, 3H); Anal. Calcd. for C₂₃ H₂₅ N₃ SO₄ : C: 62.85, H: 5.74, N: 9.57;Found: C: 62.66, H: 5.50, N: 9.38.

EXAMPLE 5 N-(4-Methoxynaphthyl)-1-indolinylcarboximide•mesylate (FormulaI: mesylate salt of R=4-methoxynaphthyl, R¹ =H, m=n=0)

White solid; mp: 151-155° C.; TLC (CHCl₃ :MeOH; 10:1); R_(f) =0.23; ¹ HNMR(CDCl₃): 8.313-7.097 (m, ArH, 9H), 6.723-6.695 (d, J=8.24 Hz, ArH, ¹H), 3.996 (s, OCH₃, 3H), 3.497-3,469 (t, CH₂, 2H), 2.971 (t, CH₂, 2H),2.733 (s, CH₃, 3H); Anal. Calcd. for C₂₁ H₂₃ N₃ SO₄ : C: 61.00, H: 5.61,N: 10.17; Found: C: 61.15, H: 5.48, N: 10.08.

EXAMPLE 6 N-(3,4-Dichlorophenyl)-1-indolinylcarboximidamide (Formula I:R=3,4dichlorophenyl, R¹ =H, m=n=0)

White solid; mp: 133-134° C.; TLC (CHCl₃ :MeOH; 10:1): R_(f) =0.29; ¹ HNMR(CDCl₃): 7.697-7.670 (d, J=8.03 Hz, ArH, 1H), 7.370-7.342 (d, J=8.48Hz, ArH, 1H), 7.208-7.090 (m, ArH, 3H), 6.939-6.811 (m, ArH, 2H),4.097-4.040 (t, J=8.37 Hz, CH₂, 2H), 3.828 (s, OCH₃, 3H), 3.182-3.125(t, J=8.37 Hz, CH₂, 2H); Anal. Calcd. for C₁₅ N₁₃ N₃ Cl₂ : C: 58.84, H:4.28, N: 13.72; Found: C: 59.00, H: 4.44, N: 13.51.

EXAMPLE 7 N-(5-Acenaphthyl)-1-(5-methoxy)-1-indolinylcarboximidamide•HCl(Formula I: hydrochloride salt of R=5-aceraphthyl, R¹ =H, m=n=1, R³=methoxy (at 5-indoline position))

Yellow solid; mp: 124-127° C.; TLC (CHCl₃ :MeOH; 10:1); R_(f) =0.30; ¹ HNNMR(CDCl₃): 7.744-6.674 (m, ArH, 8H), 3.982-3.971 (m, CH₂, 2H), 3.777(s, OCH₃, 3H), 3.433-3.334 (m, CH₂, 4H), 3.117-3.061 (t, J=8.31 Hz, CH₂,2H); Anal. Calcd. for C₂₂ H₂₂ N₃ ClO: C: 69.56, H: 5.84, N: 11.06;Found: C: 69.45, H: 5.98, N: 10.96.

EXAMPLE 8 N-(5-Acenaphthyl)-1-(5-bromo)-indolinylcarboximidamide(Formula I: R=5-acenaphthyl, R¹ =H, m=0, n=l, R³ =bromo (at 5-indolineposition))

Yellow foam; mp: 80-85° C.; TLC (CHCl₃ :MeOH; 10:1); R_(f) =0.35; ¹ HNMR(CDCl₃): 7.856-7.828 (d, J=8.52 Hz, ArH, 1H), 7.683-6.656 (d, J=8.24Hz, ArH, 1H), 7.422-7.395 (t, ArH, 1H), 7.372-7.212 (m, ArH, 2H),6.995-6.971 (d, ArH, J=7.21 Hz, 1H), 4.185-4.128 (t, J=8.51 Hz, CH₂,2H), 3.437-3.343 (m, CH₂, 2H), 3.206-3.148 (t, J=8.73 Hz, CH₂, 2H);Anal. Calcd. for C₂₁ H₁₈ N₃ Br: C: 64.30, H: 4.62, N: 10.71; Found: C:64.56, H: 4.34, N: 10.25.

EXAMPLE 9 N-(1-Naphthyl)-1-(7-ethyl)-indolinylcarboximidamide (FormulaI: R=1-naphthyl, R¹ =H, m=0, n=l, R³ =ethyl (at 7-indoline position))

White solid; mp: 160-164° C.; TLC (CHCl₃ :MeOH; 10:1); R_(f) =0.40; ¹ HNMR(CDCl₃): 7.861-7.081 (m, ArH, 10H), 3.064-3.044 (br, CH₂, 2H),2.858-2.783 (q, CH₂, 2H), 1.333-1.282 (t, J=7.54 Hz, CH₃, 3H); Anal.Calcd. for C₂₁ H₂₁ N₃ : C: 79.97, H: 6.71, N: 13.32; Found: C: 79.90, H:6.85, N: 13.33.

EXAMPLE 10 N-(4-sec-butylphenyl)-1-indolinylcarboximidamide•mesylate(Formula I: mesylate salt of R=4-sec-butylphenyl, R¹ =H, m=n=0)

White solid; TLC (CHCl₃ :MeOH; 10:1); R_(f) =0.28; ¹ H NMR (CDCl₃):7.21-6.93 (m, 3H, ArH), 4.00 (t, 2H, J=8 Hz, --Ar--CH₂ --), 3.13 (t, 2H,J=8 Hz, --NCH₂ --), 2.68 (s, 3H, CH₃ SO₃ H), 2.55-2.45 (m, 1H, --CH--),1.58-1.45 (m, 2H, --CH₂ --), 1.16 (d, 3H, J=7 Hz, --CH₃), 0.74 (t, 3H,J=7.3, --CH₃); HPLC: 98.6%; Rtn time: 18.6 minutes; MS: 294 (M⁺).

EXAMPLE 11 N-(2 ,3-dichlorophenyl)-1-indolinylcarboximidamide•HCl(Formula I: hydrochloride salt of R=2,3-dichlorophenyl, R¹ =H, m=n=0)

Light gray powder; mp: 187-187° C.; TLC (CH₂ Cl₂ :MeOH; 11:1); R_(f)=0.35; ¹ H NMR(CD₃ OD): 7.621-7.589 (q, 1H. J=3.26 Hz, ArH), 7.479-7.136(m, 6H, ArH), 4.247-4.194 (t, 2H, J=8.04 Hz, CH₂), 3.301-3.247 (t, 2H,J=8.04 Hz, CH₂); Anal. Calcd. for C₁₅ H₁₃ N₃ Cl₂ HCl 0.5H₂ O (351.67):C: 51.23, H: 4.30, N: 11.94, Cl: 30.24; Found: C: 51.14, H: 4.48, N:11.76, Cl: 30.20.

EXAMPLE 12 N-(2,3-dimethylphenyl)-1-indolinylcarboximidamide•HCl(Formula I: hydrochloride salt of R=2,3-dimethylphenyl, R¹ =H, m=n=0)

White powder; purity: 99.2% (HPLC); mp: 192-194° C.; TLC (CH₂ Cl₂ :MeOH; 11:1); R_(f) =0.48; ¹ H NMR(CD₃ OD): 7.46-7.13 (m, 7H, ArH),4.22-4.17 (t, 2H, J=8.14 Hz, CH₂), 3.30-3.25 (t, 2H, J=8.14 Hz, CH₂),2.37 (s, 3H, CH₃), 2.26 (s, 3H, CH₃).

EXAMPLE 13N-(5,6,7,8-tetrahydro-1-naphthyl)-1-indoaiylcarboximidamide•HCl (FormulaI: hydrochloride salt of R=5,6,7,8-tetrahydro-1-naphthyl, R¹ =H, m=n=0)

Light gray powder; purity: 97.5% (HPLC); mp: 175-177° C.; TLC (CH₂ Cl₂:MeOH; 11:1); R_(f) =0.53; ¹ H NMR(CD₃ OD): 7.45-7.09 (m, 7H, ArH),4.21-4.16 (t, 2H, J=8.15 Hz, CH₂), 3.29-3.24 (t, 2H, J=8.15 Hz, CH₂),2.87-2.83 (t, 3H, J=5.88 Hz, CH₃), 2.76-2.72 (t, 3H, J=5.88 Hz, CH₃).

EXAMPLE 14 N-(2-biphenyl)-1-indolinylcarboximidamide•HCl (Formula I:hydrochloride salt of R=2-biphenyl, R¹ =H, m=n=0)

Light gray powder; purity: 96.7% (HPLC); mp: 144-146° C.; TLC (CH₂ Cl₂:MeOH; 11:1); R_(f) =0.44; ¹ H NMR(CD₃ OD): 7.54-6.99 (m, 13H, ArH),3.87-3.81 (t, 2H, J=8.11 Hz, CH₂), 3.10-3.05 (t, 2H, J=7.97 Hz, CH₂);Anal. Calcd. for C₂₁ H₂₀ N₃ Cl 0.5H₂ O (349.86): C: 70.28, H: 5.89, N:11.70, Cl: 30.24; Found: C: 70.50, H: 6.03, N: 11.64.

EXAMPLE 15 N-phenyl-1-indolinylcarboximidarnide•HCl (Formula I:hydrochloride salt of R=phenyl, R¹ =H, m=n=0)

White powder; purity: 99.0% (HPLC); mp: 222-224° C.; TLC (CHCl₃ :MeOH;10:1): R_(f) =0.10; ¹ H NMR (CD₃ OD): 7.50-7.44 (m, 2H, Ar--H),7.39-7.30 (m, 5H, Ar--H), 7.26-7.21 (m, 1H, Ar--H), 7.15-7.09 (m, 1H,Ar--H), 4.22-4.17 (t, 2H, J=8.20, CH₂), 3.29-3.23 (t, 2H, J=8.20, CH₂);Anal. Calcd. for C₁₅ H₁₅ N₃ •HCl (273.77): C: 65.81, H: 5.89, N: 15.35;Found: C: 65.70, H: 5.78, N: 15.52.

EXAMPLE 16 N-(2-chlorophenyl)-1-indolinylcarboximidamide•HCl (Fornula I:hydrochloride salt of R=2-chlorophenyl, R¹ =H, m=n=0)

White powder; purity: 98.8% (HPLC); mp: 172-174° C.; TLC (CHCl₃ :MeOH;10:1): R_(f) =0.19; ¹ H NMR (CD₃ OD): 7.63-7.60 (m, 1H, Ar--H),7.47-7.35 (m, 5H, Ar--H), 7.28-7.23 (m, 1H, Ar--H), 7.16-7.11 (m, 1H,Ar--H), 4.24-4.19 (t, 2H, J=8.10, CH₂), 3.29-3.24 (t, 2H, J=8.10, CH₂);Anal. Calcd. for C₁₅ H₁₅ N₃ Cl•HCl (308.21): C: 58.46, H: 4.91, N:13.63, Cl: 23.01; Found: C: 58.64, H: 5.10, N: 13.48, Cl: 22.88.

EXAMPLE 17 N-(2-tolyl)-1-indolinylcarboximidamide•HCl (Formula I:hydrochloride salt of R=2-methylphenyl, R¹ =H, m=n=0)

Light gray powder; purity: 98.6% (HPLC); mp: 225-226° C.; TLC (CHCl₃:MeOH; 10:1): R_(f) =0.36; ¹ H NMR (CD₃ OD): 7.46-7.13 (m, 8H, Ar--H),4.23-4.17 (m, 2H, J=8.10, CH₂), 3.29-3.23 (t, J=8.10, CH₂ ; Anal. Calcd.for C₁₆ H₁₇ N₃ Cl•HCl (287.79): C: 66.78, H: 6.30, N: 14.60; Found: C:67.00, H: 6.41, N: 14.77.

EXAMPLE 18 N-(3-tolyl)-1-indolinylcarboximidamide•HCl (Formula I:hydrochloride salt of R=3-methylphenyl, R¹ =H, m=n=0)

Light gray powder; purity: 99.0% (HPLC); mp: 122-124° C.; TLC (CHCl₃:MeOH; 10:1): R_(f) =0.17; ¹ H NMR (CD₃ OD): 7.39-7.09 (m, 8H, Ar--H),4.22-4.17 (t, 2H, J=8.05, CH₂), 3.28-3.23 (t, J=8.10, CH₂); Anal. Calcd.for C₁₆ H₁₇ N₃ Cl•HCl•0.2 ether (302.62): C: 66.68, H: 6.66, N: 13.89;Found: C: 66.90, H: 6.52, N: 13.71.

EXAMPLE 19N-(2-chloro-5-ethylphenyl)-[(7-trifluoromethyl)-1,2,3,4-tetrahydroquinolinyl]carboximidamide•HCl(Formula II: R=2-chloro-5-ethylphenyl, R¹ =H, R³ =7-trifluoromethyl,n=1, m=0)

White solid; mp: 220° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.78 (s, 1H,Ar--H), 7.41-7.44 (m, 3H, Ar--H) 7.17-7.20 (br s, 1H, Ar--H), 3.89-3.93(t, J=6.5 Hz, 2H, N--CH₂), 2.88-2.92 (t, 2H, J=6.5 Hz, CH₂), 2.59-2.67(q, 2H, J=7.5 Hz, CH₂), 2.09-2.19 (dt, 2H, J=7.5 Hz, CH₂), 1.19-1.24 (t,3H, CH₃); MS (El): m/e 382 (M⁺ for free base); Anal. Calcd. for C₁₉ H₁₉CIF₃ N₃ HCl: C: 54.09, H: 4.87, N: 9.96; Found: C: 54.05, H: 5.01, N:10.00.

EXAMPLE 20N-(1-naphthyl)-[(7-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl]carboximidamide•HCl(Formula II: R=1-naphthyl, R¹ =H, R³ =7-trifluoromethyl, n=1, m=0)

White solid; mp: 215-220° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.90-8.02 (m,3H, Ar--H), 7.80 (br s, 1H, Ar--H), 7.52-7.68 (m, 4H, Ar--H), 7.37-7.41(m, 2H, Ar--H), 3.94-3.98 (t, J=6.5 Hz, 2H, N--CH₂), 2.87-2.92 (t, 2H,ArCH₂), 2.13-2.22 (q, J=6.5 Hz, 2H, CH₂); MS (El): m/e 371 (M⁻ for freebase); Anal. Calcd. for C₂₁ H₁₉ F₃ N₃ •HCl: C: 61.99, H: 4.96, N: 10.32;Found: C: 61.65, H: 4.63, N: 10.02.

EXAMPLE 21N-(1-naphthyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide•HCl(Formula II: R=1-naphthyl, R¹ =H, m=n=0)

White solid; mp: 244° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.92-8.03 (m, 3H,Ar--H), 7.49-7.68 (m, 5H, Ar--H), 7.12-7.27 (m, 3H, Ar--H), 3.89-3.93(t, J=6.5 Hz, 2H, N--CH), 2.84-2.88 (t, J=6.5 Hz, 2H, Ar--CH₂),2.11-2.19 (q, J=6.5 Hz, 2H, CH₂); MS (El): m/e 302 (M⁻ for free base);Anal. Calcd. for C₂₀ H₁₉ N₃ •HCl: C: 71.10, H: 5.97, N: 12.43; Found: C:70.83, H: 5.82, N: 12.32.

EXAMPLE 22 N-(3-biphenyl)-1-(benz[cd]indolinyl)carboximidamide•HCl(Formula IV: hydrochloride salt of R=3-biphenyl, R¹ =H, m=n=0)

Light gray solid; purity: 98.9% (HPLC); mp: 222-224° C.; TLC (CH₂ Cl₂:MeOH; 11:1): R_(f) =0.58; ¹ H NMR (CD₃ OD): 7.78-7.30 (m, 15H, Ar--H),5.60 (s, CH₂); Anal. Calcd. for C₂₄ H₁₉ N₃ •HCl•1.3H₂ O: C: 70.42, H:5.57, N: 10.26; Found: C: 70.70, H: 5.22, N: 9.96.

EXAMPLE 23 N-(2-tolyl)-1-(benz[cd]indolinyl)carboximidamide•HCl (FormulaIV: hydrochloride salt of R=2-methylphenyl, R¹ =H, m=n=0)

Light gray powder; purity: 99.0% (HPLC); mp: 132-134° C.; TLC (CH₂ Cl₂:MeOH; 11:1): R_(f) =0.58; ¹ H NMR (CD₃ OD): 7.78-7.37 (m, 10H, Ar--H),5.58 (s, 2H, CH₂), 2.41 (s, 3H, CH₃).

EXAMPLE 24 N-(2,3-dimethylphenyl)-1-benz[cd]indolinylcarboximidamide•HCl(Formula IV: hydrochloride salt of R=2,3-dimethylphenyl, R¹ =H, m=n=0)

Gray powder; purity: 97.6% (HPLC); mp: 236-238° C.; TLC (CHCl₃ :MeOH;10:1): R_(f) =0.27; ¹ H NMR (CD₃ OD): 7.79-7.23 (m, 9H, Ar--H), 5.58 (s,2H, CH₂), 2.40 (s, 3H, CH₃), 2.31 (s, 3H, CH₃); Anal. Calcd. for C₂₀ H₁₉N₃ •HCl (338.84): C: 71.10, H: 5.97, N: 12.44; Found: C: 71.16, H: 5.94,N: 12.22.

EXAMPLE 25 N-(2,5-dimethylphenyl)-1-benz[cd]indolinylcarboximidamide•HCl(Formula IV: hydrochloride salt of R=2,5-dimethylphenyl, R¹ =H, m=n=0)

White solid; purity: 97.4% (HPLC); mp: 132-134° C.; TLC (CHCl₃ :MeOH;10:1): R_(f) =0.28; ¹ H NMR (CD₃ OD): 7.76-7.21 (m, 9H, Ar--H), 5.57 (s,2H, CH₂), 2.37 (s, 3H, CH₃), 2.35 (s, 3H, CH₃); Anal. Calcd. for C₂₀ H₁₉N₃ •HCl•0.4H₂ O (345.06): C: 69.62, H: 6.08, N: 12.18; Found: C: 69.66,H: 5.70, N: 11.85.

EXAMPLE 26 N-(1-naphthyl)-1-benz[cd]indolinylcarboximidamide•HCl(Formula IV: hydrochloride salt of R=1-naphthyl, R¹ =H, m=n=0)

Light gray solid; purity: 98% (HPLC); mp: 250-251° C.; R_(f) =0.43chloroform/methanol 20/1); ¹ H NMR (CD₃ OD): 8.10-7.40 (m, 13H, Ar--H),5.68 (s, 2H, ArCH₂); HRMS: 323.1419 (cal: 323.1422 for C₂₂ H₁₇ N₃).

EXAMPLE 27 N-(3-ethylphenyl)-1-benz[cd]indolinylcarboximidamide•mesylate(Formula IV: mesylate salt of R=3-ethylphenyl, R¹ =H, m=n=0)

Light gray solid; purity: 98% (HPLC); mp: 158-159° C.; R_(f) =0.38(chloroform/methanol 10/1); ¹ H NMR (CD₃ OD): 7.76-7.25 (m, 1OH, Ar--H),5.56 (s, 2H, ArCH₂), 2.68-2.74 (m, 5H, CH₂ +CH₃ SO₃ H), 1.26 (t, 3H,CH₃, J=7.45 Hz); Anal. Calcd. for C₂₀ H₁₉ N₃ •CH₃ SO₃ H: C: 63.46, H:5.83, N: 10.57; Found: C: 63.30, H: 5.74, N: 10.39.

EXAMPLE 28 N-(naphth-1-yl)-1-(6-hydro)phenanthridinylcarboximidamide•HCl(Formula V: hydrochloride salt of R=1-naphthyl, R¹ =H, m=n=0)

White solid; purity: 93.7% (HPLC); mp: 234-236° C.; R_(f) =0.38(chloroform/methanol 10/1); ¹ H NMR (CD₃ OD): d ppm 7.92-7.32 (m, 15H,Ar--H), 4.97 (s, 2H, ArCH₂); Anal. Calcd. for C₂₄ H₁₉ N₃ •HCl: C: 74.70,H: 5.22, N: 10.88; Found: C: 74.86, H: 5.40, N: 10.82.

EXAMPLE 29 N-(2-naphthyl)-1-indolinyl-carboximidamide•hydrochloride(Formula I: hydrochloride salt of R=2-naphthyl, R¹ =H,m=n=0)

White plate; purity: 99.6% (HPLC); mp: 256-258° C.; TLC (CH₂ Cl₂ :MeOH;10:1): R_(f) =0.19; ¹ H NM (CD₃ OD): 8.00-7.97 (d, 1H, J=8.8 Hz, Ar--H),7.92-7.81 (m,3H, Ar--H), 7.55-7.36 (m, 5H, Ar--H), 7.24-7.12 (m, 2H,Ar--H), 4.27-4.22 (t, 2H, J=8.1 Hz, CH₂), 3.30-3.25 (t, 2H, J=8.1 Hz,CH₂). Anal. Calcd. for C₁₉ H₁₇ N₃ •HCl (323.83): C, 70.47, H, 5.60, N,12.98; Found: C, 70.26, H, 5.76, N, 12.76.

EXAMPLE 30 N-(3-biphenyl)-1-indolinyl-carboximidamide (Formula I:R=3-biphenyl, R¹ =H, m=n=0)

White powder; purity: 97.1% (HPLC); mp: 148-150°; TLC (CH₂ Cl₂ : MeOH;0:1): R_(f) =0.18; ¹ H NMR (CD₃ OD): 7.63-7.59 (m, 2H, Ar--H), 7.53-7.24(m, 8H, Ar--H), 7.16-7.10 (m, 2H, Ar--H), 6.99-6.94 (m, 1H, Ar--H),4.15-4.10 (t, 2H, J=8.2 Hz, CH₂), 3.20-3.15 (t, 2H, J=8.2 Hz, CH₂).Anal. Calcd. for C₂₁ H₁₉ N₃ •0.2EtOAc (331.03): C, 79.10, H, 6.27, N,12.69; Found: C, 78.92, H, 6.02, N, 12.96.

EXAMPLE 31N-(5-methoxynaphthyl)-1-indolinyl-carboximidmide•hydrochloride (FormulaI: HCl salt of R=5-methoxynaphthyl, R¹ =H,m=n=0)

White solid; purity: 97.87% (HPLC); TLC (CHCl₃ : MeOH; 10:1): R_(f)=0.15; mp: 236-239° C.; ¹ H NMR (CD₃ OD): 8.38-8.34 (d, 1H, J=7.3 Hz,Ar--H), 7.59-7.50 (m, 5H, Ar--H), 7.40-7.38 (d, 1H, J=6.8 Hz, Ar--H),7.29-7.24 (td, 1H, J=8,1.4 Hz. Ar--H), 7.17-7.11 (td, 1H, J=7.4,1.0 Hz,Ar--H), 7.06-7.03 (dd, 1H, J=6.4,1.3 Hz, Ar--H), 4.30-4.25 (t, 2H, J=8.0Hz, CH₂), 4.04 (s, 3H, OCH₃), 3.34-3.29 (t, 2H, J=8.0 Hz, CH₂). Annal.Calcd. for C₂₀ H₁₉ N₃ O•HCl (353.86): C, 67.89, H, 5.70, N, 11.88;Found: C, 67.65, H, 5.61, N, 11.63.

EXAMPLE 32N-(2-methylsulfinylphenyl)-1-indolinyl-carboximidamide•hydrochloride(Formula I: HCl salt of R=2-(CH₃ SO)phenyl, R¹ =H, m=n=0)

Light yellow powder; purity: 99.6% (HPLC); TLC (CHCl₃ : MeOH; 10:1):R_(f) =0.5; ¹ H NMR (CD₃ OD): 8.01-7.98 (dd, I1, J=2.7,7.7 Hz, Ar--H),7.76-7.67 (m, 2H, Ar--H), 7.57-7.54 (m, 1H, Ar--H), 7.48-7.45 (d, 1H,J=7.7 Hz, Ar--H), 7.41-7.38 (d, 1H, J=6.6 Hz, Ar--H), 7.32-7.26 (t, 3H,J=8.2 Hz, Ar--H), 7.19-7.14 (m, 1H, Ar--H), 4.27-4.19 (m, 2H, CH₂),3.33-3.27 (t, 2H, J=8.4 Hz, CH₂), 2.92 (s, 3H, CH₃).

EXAMPLE 33N-(1-naphthyl)-(6-methyl-1,2,3,4-tetrahydroquinolinyl)carboximidamidehydrochloride (Formula II: HCl salt of R=1-naphthyl, R¹ =H, X=CH₂, R³=CH₃, n=1, m=0)

Light purple solid: mp 205-206° C.; R_(f) =0.364 (9:2 CHCl₃ /MeOH); ¹ HNMR (300 MHz, CD₃ OD) δ 7.92-8.0 (m, 3H, Ar--H), 7.51-7.68 (m, 4H,Ar--H), 7.37-7.40 (d, 1H, J=8.25 Hz, Ar--H), 7.02-7.08 (m, 2H, Ar--H),3.87-3.91 (t, 2H, J=12.94 Hz, CH₂), 2.80-2.84 (t, 2H, J=12.91 Hz, CH₂),2.29 (s, 3H, CH₃), 2.11-2.17 (m, 2H, CH₂). MS(Cl): m/e 316 (M+ for freebase). Anal. Calcd. for C₂₁ H₂₁ N₃ •HCl: C, 71.68, H, 6.30, N, 11.94.Found: C, 71.73, H, 6.51, N, 12.07.

EXAMPLE 34 N-(1-naphthyl)-N'-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide hydrochloride (Formula II: HCl saltof R=1-naphthyl, R¹ =H, X=S, m=n=0)

White solid: mp 245-246° C.; R_(f) =0.13 (10:1 CHCl₃ /MeOH); ¹ H NMR(300 MHz, CD₃ OD) δ 7.92-8.20 (m, 3H, Ar--H), 7.48-7.71 (m, 5H, Ar--H),7.28-7.35 (m, 1H, Ar--H), 7.12-7.20 (m, 2H, Ar--H), 4.16-4.22 (m, 2H,CH₂), 3.40-3.47 (m, 2H, CH₂). MS(Cl): m/e 320 (M+ for free base). Anal.Calcd. for C₁₉ H₁₇ N₃ S•HCl: c, 64.12, H, 5.10, N, 11.81. Found: C,64.28, H, 5.20, N, 11.69.

EXAMPLE 35N-(2,5-dibromophenyl)-(7-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)carboximidamidehydrochloride (Formula II: HCl salt of R=2,5-dibromophenyl, R¹ =H,X=CH₂, R³ =CF₃, n=1, m=0)

Cream colored solid: mp 201-202° C.; R_(f) =0.354 (Eth. Ac.); ¹ H NMR(300 MHz, CD₃ OD) δ 7.79 (s, 1H, Ar--H), 7.45-7.48 (m, 1H, Ar--H),7.25-7.28 (d, 1H, J=7.97 Hz, Ar--H), 7.12-7.15 (m, 2H, Ar--H), 7.03-7.07(m, 1H, Ar--H), 3.78-3.82 (t, 2H, J=11.96 Hz, CH₂), 2.84-2.89 (t, 2H,J=13.19 Hz, CH₂, 2.01-2.08 (m, 2H, CH₂). MS(Cl): m/e 478 (M+ for freebase). Anal. Calcd. for C₁₇ H₁₄ Br₂ F₃ N₃ •HCl: C, 39.76, H, 2.94, N,8.18. Found: C, 39.57, H, 2.96, N, 7.98.

EXAMPLE 36N-(2,3-difluorophenyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamnidehydrochloride (Formula II: HCl salt of R=2,3-fluorophenyl, R¹ =H, X=CH₂,m=n=0)

White solid: mp 194-195° C.; R_(f) =0.135 (10:2 CHCl₃ /MeOH); ¹ H NMR(300 MHz, CD₃ OD) δ 7.34-7.37 (m, 1H, Ar--H), 7.12-7.27 (m, 6H, Ar--H),3.83-3.87 (t, 2H, J=13.0 Hz, CH₂), 2.82-2.86 (t, 2H, J=13.19 Hz, CH₂),2.06-2.15 (m, 2H, CH₂). MS(Cl): m/e 288 (M+ for free base). Anal. Calcd.for C₁₆ H₁₅ F₂ N₃ •HCl: c, 59.36, H, 4.98, N, 12.98. Found: C, 59.44, H,4.97, N, 12.74.

EXAMPLE 37N-(2-trfluoromethoxyphenyl)-(1,2,3,4-tetrahydroquinolinyl)carboximiidehydrochloride (Formula II: HCl salt of R=2-trifluromethoxyphenyl, R¹ =H,X=CH₂, m=n=0)

White solid: mp 80-82° C.; R_(f) =0.115 (10:1 CHCl₃ /MeOH); ¹ H NMR(300MHz, CD₃ OD) δ 7.46-7.52 (t, 1H, J=16.42 Hz, Ar--H), 7.15-7.35 (m,7H, Ar--H), 3.82-3.86 (t, 2H, J=12.98 Hz, CH₂), 2.82-2.86 (t, 2H,J=12.91 Hz, CH₂), 2.11-2.17 (m, 2H, CH₂). MS(Cl): m/e 336 (M⁺ for freebase). Anal. Calcd. for C₁₇ H₁₆ F₃ N₃ O•HCl: C, 54.92, H, 4.61, N,11.30. Found: C, 55.10, H, 4.78, N, 11.44.

EXAMPLE 38N-(2-biphenyl)-1-benz[cd]indolinyl-carboximidamide•hydrochloride(Formula IV: HCl salt of R=2-biphenyl, R¹ =H, m=n=0)

Light grey powder; purity: 94.0% (HPLC); TLC (CHCl₃ :MeOH; 10:1): R_(f)=0.25; mp: 143-145° C.; ¹ H NMR (CD₃ OD): 7.73-7.70 (d, 1H, J=8.2 Hz,Ar--H), 7.61-7.32 (m, 13H, Ar--H), 7.08-7.06 (d, 1H, J=7.1 Hz, Ar--H),5.19 (s, 2H, CH₂). Anal. Calcd. for C₂₄ H₁₉ N₃ •HCl (385.89): c, 74.70,H, 5.22, N, 10.89; Found: C, 74.60, H, 5.40, N, 10.61.

EXAMPLE 39N-(3.5-dichlorophenyl)-1-tetrahydrobenz[cd]indolinyl-carboximidamide•hydrochloride(Formula VII: HCl salt of R=3,5-dichlorophenyl, R¹ =H, m=n=0)

White solid; purity: 98.7% (HPLC); TLC (CHCl₃ : MeOH; 10:1): R_(f)=0.28; ¹ H NMR (CD₃ OD): 7.39-7.35 (m, 3H, Ar--H), 7.19-7.14 (t, 1H,J=7.3 Hz, Ar--H), 7.11-7.08 (d, 1H, J=7.4 Hz, Ar--H), 6.95-6.93 (d, 1H,J=6.9HZ, Ar--H), 4.44-4.38 (dd, 1H, J=8.1,9.9 Hz, NCH), 3.44-3.40 (dd,1H, J=8.1,9.9 Hz, NCH), 2.94-2.85 (m, 1H, CH), 2.75-2.69 (m, 1H, CH),2.27-2.12 (m, 2H, CH₂), 1.86-1.80 (m, 1H, CH), 1.41-1.29 (m, 1H, CH).Calcd. for C₁₈ H₁₇ N₃ Cl₂ •HCl (382.73): C, 56.49, H, 4.74, N, 11.98,Cl, 27.79; Found: C, 56.44, H, 5.00, N, 10.99, Cl, 27.61.

EXAMPLE 40N-(2,5-dibromophenyl)-(2,3,4,5-tetrahydro-[1,5]-benzothiazin-5-yl)carboximidamidehydrochloride (Formula VI: HCl salt of R=2,5-dibromophenyl, R¹ =H, X=S,m=n=0)

Whitish solid: mp 216-217° C.; ¹ H NMR (300 MHz, CD₃ OD) δ 7.4-7.8 (m,7H, Ar--H), 4.3--4.65 (brs, 1H, CH₂), 3.2-3.4 (brs, 1H, CH₂), 2.7-3.1(m, 2H, CH₂), 2.1-2.4 (m, 2H, CH₂). MS(Cl): m/e 442 (M⁺ +H for freebase). Anal. Calcd. for C₁₆ H₁₅ Br₂ N₃ S•HCl: C, 40.23, H, 3.38, N,8.80; Found: C, 40.08, H, 3.10, N, 8.73.

EXAMPLE 41 Synthesis of5,6,11,12-tetrahydrodibenz[b,f]azocincarboximidamide•hydrochloride##STR34##

By method indicated above in Example 3, part 3 using5,6,11,12-tetrahydrodibenz[b,f]azocine•HCl.

White solid: mp: 238-240° C., TLC (CHCl₃ :MeOH; 10:1); R_(f) =0.25; ¹ HNMR (CD₃ OD) δ ppm 7.1 (m, Ar--H, 8H), 5.28 (d, CHN, 1H), 4.58 (d, CHN,1H), 3.20 (m, CH₂, 1H), 3.0 (m, CH₂, 1H); Mass /CI--NH₃ : MH⁺ 252; Anal.Calcd. for C₁₆ H₁₈ N₃ Cl•0.25H₂ O: C, 65.75, H, 6.38, N, 14.38; Found:C, 65.55, H, 6.37, N, 14.94.

EXAMPLE 42 Synthesis ofN-(4'-sec-burylphenyl)-1-(5,6,11,12-tetrahydrodibenz[b,f]azocin)-carboximidamide•hydrochloride

Part A: Preparation of 5,6,11,12-tetrahydrodibenz[b,f]azocin-cyanamide

By method indicated in Example 2, part 1 above using5,6,11,12-tetrahydrodibenz[b,f]azocine. ##STR35## Part B: Preparation ofN-(4'-sec-butylphenyl)-1-(5,6,11,12-tetrahydrodibenz[b,f]azocin)-carboximidamide•hydrochloride##STR36##

By method indicated in Example 2, part 2 above using5,6,11,12-tetrahydrodibenz[b,f]azocin-cyanamide, sec-butylaniline andone equivalent of aluminum chloride.

Oil, TLC (CHCl₃ :MeOH; 10:0.5); R_(f) =0.25; ¹ H NMR (CDCl₃) δ ppm 7.1(m, Ar--H, 12H), 5.4 (br, CHN, 1H), 4.6 (br, CHN, 1H), 3.25 (br, CH₂,2H), 3.0 (br, CH₂, 2H), 2.55 (m, CH, 1H), 1.60 (m, CH₂, 2H), 1.2 (d, CH₃CH₂, 3H), 0.8 (t, CH₃ CH, 3H); Mass /CI--NH₃ : MH⁺ 384.

EXAMPLE 43 10,11-dihydro-[5H]-diben[b,f]azepinylcarboximidamidehydrochloride

White solid: mp 120-121° C.; ¹ H NMR (300 MHz, CD₃ OD) δ 7.31-7.46 (m,8H, Ar--H), 3.23-3.36 (brs, 2H, Ar--CH₂), 2.80-2.93 (brs, 1H, Ar--CH₂);MS(Cl): m/e 238 (M⁺ for free base); Anal. Calcd. for C₁₅ H₁₅ N₃ •HCl: C,60,99, H, 6.28, N, 14.22; Found: C, 60.91, H, 6.17, N, 14.29.

EXAMPLE 44 N-(1-naphthyl)-dibenzo[b,f]azepinylcarboximidamidehydrochloride

White solid; mp 230° C.; ¹ H NMR (300 MHz, CD₃ OD) δ 7.94-7.99 (m, 2H,Ar--H), 7.79-7.87 (m, 2H, Ar--H), 7.62-7.69 (m, 5H, Ar--H), 7.51-7.61(m, 5H, Ar--H), 7.44-7.47 (m, 1H, Ar--H), 7.33-7.36 (brs, 2H, CH=CH);MS(Cl): m/e 262 (M⁺ +H for free base); Anal. Calcd. for C₂₅ H₁₉ N₃ •HCl:C, 75.46, H, 5.07, N, 10.56; Found: C, 75.59, H, 5.03, N, 10.55.

EXAMPLE 45 N-(4-butoxyphenyl)-dibenzo[b,f]azepinylcarboximidarnidehydrochloride

White solid: mp 190-192° C.; R_(f) =0.269 (10:2 CHCl₃ /MeOH); ¹ H NMR(300 MHz, CD₃ OD) δ 7.49-7.73 (m, 8H, Ar--H), 7.19 (s, 2H, Ar--H),7.07-7.10 (m, 2H, Ar--H), 6.92-6.95 (m, 2H, Ar--H), 3.93-3.97 (t, 2H,J=13 Hz, 2H, CH₂), 1.68-1.78 (m, 2H, CH₂), 1.40-1.52 (m, 2H, CH₂),0.928-0.977 (t, 3H, J=14.71 Hz, CH₃); MS(C1): m/e 384 (M⁺ for freebase); Anal. Calcd. for C₂₅ H₂₅ N₃ O•CH₃ SO₃ H: C, 65.11, H, 6.09, N,8.76; Found: C, 61.16, H, 6.45, N, 8.20.

EXAMPLE 46N-(2-chloro-5-methylsulfinylphenyl)-1-(6-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)carboximidaimidehydrochloride (Formula II: HCl salt of R=2-chloro-5-methylsulfmylphenyl,R¹ =H, X=CH₂, R³ =6-trifluoromethyl, n=1, m=0)

The title compound was prepared by oxidiation of the correspondingsulfide precursor (i.e.(N-(2-chloro-5-methylthiophenyl)-1-(6-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)-carboxitidamide)with 30% hydrogen peroxide in methanol at reflux for 24 hours, followedby column chrornatography over silica gel.

White solid: mp 188-190° C.; R_(f) =0.12 (10:1 CHCl₃ /MeOH); ¹ H NMR(300 MHz, CD₃ OD) δ 7.476-7.743 (m, 7H, Ar--H), 3.904-3.946 (t, J=6 Hz,2H, CH), 2.799 (s, 3H, CH₃), 2.100-2.186 (m, 2H, CH₂); MS(Cl): m/e 417(M+ for free base); Anal. Calcd. for C₁₈ H₁₇ ClF₃ N₃ OS•HCl: C, 47.80,H, 4.01, N, 9.29; Found: C, 47.86, H, 4.25, N, 9.16.

EXAMPLE 47N-(1-naphthyl)-1-(2,3-dihydro-1-oxo-6-trifluoromethylbenzo[1,4]thiazin-4-yl)carboximaidamidemesylate (Formula II": mesylate salt of R=1-naphthyl, R¹ =H,X=S--(O)--R³ =6-trifluoromethyl, n=1, m=0)

The title compound was prepared by oxidiation of the correspondingsulfide precursor (i.e.N-(1-naphthyl)-1-(2,3-dihydro-6-trifluoromethylbenzo[1,4]thiazin-4-yl)carboximidamide) with sodium periodate in acetonitrile:water (1:1) atroom temperature for 24 hours, then conversion to free base with 1N NaOHfollowed by column chromatography over silica gel and conversion to themesylate salt with methane sulfonic acid.

White solid: mp 231-234° C.; R_(f) =0.45 (9:1 CHCl₃ /MeOH); ¹ H NMR (300MHz, CD₃ OD) δ 7.96-8.03 (m, 3H, Ar--H), 7.58-7.63 (m, 1H, Ar--H),7.4014 7.52 (m, 3H, Ar--H), 7.28-7.39 (d, J=6 Hz, 1H, Ar--H), 7.02-7.11(d, J=6 Hz, 1H, Ar--H), 4.44-4.52 (brs, 1H, CH₂), 4.02-4.20 (brs, 1H,CH₂), 3.19-3.40 (brs, 1H, CH₂); MS(Cl): m/e 404 (M⁺ for free base);Anal. Calcd. for C₂₀ H₁₆ F₃ N₃ OS•HCl: C, 45.41, H, 4.76, N, 7.57;Found: C, 45.09, H, 4.40, N, 7.29.

EXAMPLE 48

In vivo Anticonvulsant activity in the DBA/2 mouse model (Mouseaudiogenic assay)

The in vivo potency of compounds of the invention is exemplified by datasummarized in the Table I below and obtained pursuant to the followingprotocol.

Compounds were tested for their effectiveness in preventing seizures inDBA/2 mice which have a unique sensitivity to auditory stimulation.Exposure to loud high-frequency sounds can trigger seizure activity inthese animals. This sensitivity develops from postnatal day 12 and peaksaround day 21 and slowly diminishes as the animals mature. The unusualresponse to auditory stimulation in this strain of mouse is believed tobe due to a combination of early myelination (causing an unusually lowexcitatory threshold) and delayed development of inhibitory mechanisms.

Mice were injected intraperitoneally with the compound specified inTable I below or with vehicle control, 30 minutes prior to being placedin a bell jar and turning on the auditory stimulus (12 KHz sine wave at110-120 db). Administered doses are specified in Table I as milligram ofcompound per kilogram bodyweight of mouse. The auditory stimulus wasleft on for 60 seconds and mice reactions were time and recorded.Percentage inhibition was determined with reference to vehicle controls.Results are shown in the Table I below. "FB" refers to free base.

                                      TABLE I                                     __________________________________________________________________________                           Audiogenic Response                                    Example No.                                                                         Compound Name    Dose (mg/kg)                                                                         % Inhib.                                                                           Salt                                       __________________________________________________________________________    2     N-(1-naphthyl)-1-                                                                              2      82   FB                                                           indolinylcarboximidamide                                                                          100                                     4          N-(4-benzyloxyphenyl)-1-                                                                                   mesylate                                                indolinylcarboximidamide                                    5          N-(40-methoxynaphthyl)-1-                                                                                  mesylate                                               indolinylcarboximidamide                                                                            68                                                                            87                              20     6          N-(3,4-dichlorophenyl)-1-                                                                                    FB                                               indolinylcarboximidamide                                                                                83                                     7          N-(5-acenaphthyl)-1-(5-methoxy)-                                                              10             FB                                              indolinylcarboximidamide                                          8          N-(5-acenaphthyl)-1-(5-bromo)-                                                                  20                                                                                         FB                                             indolinylcarboximidamide                                           9          N-(4-sec-butylphenyl)-1-                                                                                   mesylate                                         indolinylcarboximidamide                                           11         N-(2,3-dichlorophenyl)-1-                                                                                    HCl                                           indolinylcarboximidamide                                            12         N-(2,3-dimethylphenyl)-1-                                                                                    HCl                                          indolinylcarboximidamide                                                                                    67                                                                            23                       2             13         N-(5,6,7,8-tetrahydro-1-naphthyl)-1-                                                      20                 HCl                                          indolinylcarboximidamide                                                                                    48                                     14         N-(2-biphenyl)-1-                                                                                            HCl                                                   indolinylcarboximidamide                                    20         N-(1-naphthyl)-[(7-trifluoromethyl-                                                       4                  HCl                                                  1,2,3,4-tetrahydroquinolinyl)                                                  carboximidamide]                                            21         N-(1-naphthyl)-1,2,3,4-                                                                                      HCl                                                   tetrahydroquinolinyl)                                                                              62                                                      carboximidamide                                                                                     13    1                                22         N-(3-biphenyl)-N-                                                                                            HCl                                                 (benz[cd]indolinyl)carboximidamide                            23         N-(2-tolyl)-N-                                                                                               HCl 4                                              (benz[cd]indolinyl)carboximidamide                                                      2          61                                                               1            53                                        --       N-(1-naphthyl)-[6-methyl-1,2,3,4-                                                                4             HCl                                            tetrahydroquinolinyl)carboximidamide                               --       N-(2-chloro-5-ethylphenyl)-[7-                                                                     20                                                                                        HCl                                           trifluoromethyl-1,2,3,4-                                                                                4410                                               tetrahydroquinolinyl)                                                        carboximidamide]                                                      25         N-(1-naphthyl)-1-                                                                                            HCl10                                      benz[cd]indolinylcarboximidamide                                                                  5        59                                        --       N-(1-naphthy1)-1,2,3,4-                                                                                        HCl                                       tetrahydroisoquinolinyl)                                                      carboximidamide                                                         __________________________________________________________________________

This invention has been described in detail with reference to preferredembodiments thereof. However, it will be appreciated that those skilledin the art, upon consideration of this disclosure, may makemodifications and improvements within the spirit and scope of theinvention.

What is claimed is:
 1. A compound of the following formula: ##STR37##wherein R and R¹ are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedaminoalkyl, substituted or unsubstituted alkylsulfinyl or substituted orunsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclicaryl, substituted or unsubstituted aralkyl, or a substituted orunsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms,with at least one of R and R¹ being other than hydrogen;each R³ isindependently hydrogen, halogen, hydroxyl, azido, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted aminoalkyl, substituted or unsubstituted carbocyclicaryl, or substituted or unsubstituted aralkyl having at least about 6ring carbon atoms; X is --O--, --S--, or substituted or unsubstituted--N--; n is 0, 1, 2, 3 or 4; and pharmaceutically acceptable saltsthereof.
 2. A compound of the following formula: ##STR38## wherein R andR¹ are each independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylthio, substituted or unsubstituted aminoalkyl,substituted or unsubstituted alkylsulfinyl or substituted orunsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclicaryl, substituted or unsubstituted aralkyl, or a substituted orunsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3rings, 3 to 8 ring members in each ring and from 1 to 3 heteroatoms;each R² and each R³ is independently hydrogen, halogen, hydroxyl,azido, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is sulfinyl or sulfonyl; mand n are each independently 0,1,2,3 or 4; and pharmaceuticallyacceptable salts thereof.
 3. A compound of the following formula:##STR39## wherein R and R¹ are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkylthio, substituted orunsubstituted aminoalkyl, substituted or unsubstituted alkylsulfinyl orsubstituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedcarbocyclic aryl, substituted or unsubstituted aralkyl, or a substitutedor unsubstituted heteroaromatic or heteroalicyclic group having from 1to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 heteroatoms;each R² and each R³ is independently hydrogen, halogen, hydroxyl,azido, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is sulfmyl or sulfonyl; mand n are each independently 0,1,2,3 or 4; or pharmaceuticallyacceptable salts thereof.
 4. A compound of any one of claim 1 thatis:N-(1-naphthyl)-4-(2,3-dihydro-[1 ,4]-benzothiazinyl)carboximidamide;N-(1-naphthyl)-4-(2,3-dihydro-[1,4]-benzoxazinyl)carboximidamide;N-(2,5-dibromophenyl)-4-(2,3-dihydro-6-trifluoromethyl-[1,4]-benzothiazinyl)carboximidamide;N-(2-fluoro-5-trifluoromethylphenyl)-4-(6-chloro-[1,4]-benzothiazinyl)-carboximidamide;N-(2,5-dibromophenyl)-4-(6-chloro-[1,4]-benzothiazinyl)carboximidamide;N-(1-naphthyl)-4-(6-chloro-2,3-dihydro-[1,4]-benzothiazinyl)carboximidamideN-(5-acenaphthyl)-4-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;N-(2,3-difluorophenyl)-N-methyl-4-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;N-(1-naphthyl)-4-(6-trifluoromethyl-2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;N-(5,6,7,8-tetrahydro-1-naphthyl)-4-(2,3-dihydrobenzo-[1,4]-thiazinyl)carboximidamide;N-(3-biphenyl)-4-(2,3-dihydrobenzo-[1,4]-thiazinyl)carboximidamide;N-(2-naphthyl)-4-(2,3-dihydrobenzo-[1,4]-thiazinyl)carboximidamide;N-(3,5-dichlorophenyl)-4-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;andN-(2,3-difluorophenyl)-4-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;oror a pharmaceutically acceptable salt of said compounds.
 5. A compoundof claim 3 that isN-(2,5-dibromophenyl)-4-(2,3-dihydro-4-oxo-6-trifluoromethyl-[1,4]-benzothiazinyl)-carboximidamide;N-(2,5-dibromophenyl)-4-(2,3-dihydro-1-dioxo-6-trifluoromethyl)-([1,4]-bezothiazinyl)carboximidarmide;orN-(1-naphthyl)-4-(2,3-dihydro-6-trifluoromethylbenzo[1,4]-1-oxo-thiazinyl)carboximidamide;ora pharmaceutically acceptable salt of said compounds.
 6. A compound ofany one of claims 1, 2 or 3 wherein R is substituted or unsubstitutedcarbocyclic aryl, substituted or unsubstituted aralkyl, or a substitutedor unsubstituted heteroaromatic or heteroalicyclic group.
 7. A compoundof any one of claims 1, 2 or 3 wherein R is substituted or substitutedcarbocyclic aryl.
 8. A compound of any one of claims 1, 2 or 3 wherein Ris substituted or urisubstituted phenyl or naphthyl.
 9. A compound ofany one claims 1, 2 or 3 wherein R is phenyl or naphthyl substituted atone or more ring positions by halogen hydroxyl, azido, alkyl, alkenyl,alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aminoalkyl,carbocyclic aryl, or aralkyl.
 10. A compound of any one of claims 1, 2or 3 wherein R¹ is hydrogen or substituted or unsubstituted alkyl,substituted or unsubstitued alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylthio, substituted or unsubstituted aminoalkyl,substituted or unsubstituted alkylsulfinyl, or substituted orunsubstituted alkylsulfonyl.
 11. A compound of any one of claims 1, 2 or3 wherein R¹ is hydrogen or substituted or unsubstituted alkyl.
 12. Acompound of any of the claims 1, 2 or 3 that is optically active.
 13. Acompound of claim 2 or 3 where the compound contains an optically active--S(O)-- group.
 14. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of any one of claims1, 2, 3, 5 or
 6. 15. A method of treating a neurodegenerative diseasecomprising administering to a mammal suffering from or susceptible tosaid disease a therapeutically effective amount of a compound of thefollowing formula: ##STR40## wherein R and R¹ are each independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted aminoalkyl, substituted or unsubstitutedalkylsulfinyl or substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl,or a substituted or unsubstituted heteroaromatic or heteroalicyclicgroup having from 1 to 3 rings, 3 to 8 ring members in each ring andfrom 1 to 3 hetero atoms;each R² and each R³ are each independentlyhydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedaminoalkyl, substituted or unsubstituted carbocyclic aryl, orsubstituted or unsubstituted aralkyl having at least about 6 ring carbonatoms; X is --O--, --S--, or substituted or unsubstituted --N--; m and nare each independently 0,1,2,3 or 4; and pharmaceutically acceptablesalts thereof.
 16. A method of treating a neurodegenerative diseasecomprising administering to a mammal suffering from said disease atherapeutically effective amount of a compound of the following formula:##STR41## wherein R and R¹ are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkylthio, substituted orunsubstituted aminoalkyl, substituted or unsubstituted alkylsulfinyl orsubstituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedcarbocyclic aryl, substituted or unsubstituted aralkyl, or a substitutedor unsubstituted heteroaromatic or heteroalicyclic group having from 1to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 heteroatoms;each R² and each R³ are each independently hydrogen, halogen,hydroxyl, azido, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is sulfinyl or sulfonyl; mand n are each independently 0,1,2,3 or 4; and pharmaceuticallyacceptable salts thereof.
 17. A method of treating Alzheimer's disease,Parkinson's disease, Huntington's disease, Amyotrophic LateralSclerosis, Down's Syndrome or Korsakoff's disease, Cerebral Palsy, orepilepsy, comprising administering to a mammal suffering from orsusceptible to said disease a therapeutically effective amount of acompound of the formula: ##STR42## wherein R and R¹ are eachindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted aminoalkyl, substituted orunsubstituted alkylsulfinyl or substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted carbocyclic aryl,substituted or unsubstituted aralkyl, or a substituted or unsubstitutedheteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8ring members in each ring and from 1 to 3 hetero atoms;each R² and eachR³ are each independently hydrogen, halogen, hydroxyl, azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is --O--, --S--, orsubstituted or unsubstituted --N--; m and n are each independently0,1,2,3 or 4; and pharmaceutically acceptable salts thereof.
 18. Amethod of treating Alzheimer's disease, Parkinson's disease,Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome orKorsakoff's disease, Cerebral Palsy, or epilepsy, comprisingadministering to a mammal suffering from said disease a therapeuticallyeffective amount of a compound of the formula: ##STR43## wherein R andR¹ are each independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylthio, substituted or unsubstituted aminoalkyl,substituted or unsubstituted alkylsulfinyl or substituted orunsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclicaryl, substituted or unsubstituted aralkyl, or a substituted orunsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3rings, 3 to 8 ring members in each ring and from 1 to 3 heteroatoms;each R² and each R³ are each independently hydrogen, halogen,hydroxyl, azido, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is sulfnyl or sulfonyl; mand n are each independently 0,1,2,3 or 4; and pharmaceuticallyacceptable salts thereof.
 19. A method of treating nerve cell death ordegeneration comprising administering to a mammal suffering from orsusceptible to nerve cell death or degeneration a therapeuticallyeffective amount of a compound of the formula: ##STR44## wherein R andR¹ are each independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylthio, substituted or unsubstituted aminoalkyl,substituted or unsubstituted alkylsulfinyl or substituted orunsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclicaryl, substituted or unsubstituted aralkyl, or a substituted orunsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3rings, 3 to 8 ring members in each ring and from 1 to 3 heteroatoms;each R² and each R³ are each independently hydrogen, halogen,hydroxyl, azido, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is --O--, --S--, orsubstituted or unsubstituted --N--; m and n are each independently0,1,2,3 or 4; and pharmaceutically acceptable salts thereof.
 20. Amethod of treating or preventing nerve cell death or degenerationcomprising administering to a mammal suffering from or susceptible tonerve cell death or degeneration a therapeutically effective amount of acompound of the formula: ##STR45## wherein R and R¹ are eachindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted aminoalkyl, substituted orunsubstituted alkylsulfinyl or substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted carbocyclic aryl,substituted or unsubstituted aralkyl, or a substituted or unsubstitutedheteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8ring members in each ring and from 1 to 3 hetero atoms;each R² and eachR³ are each independently hydrogen, halogen, hydroxyl, azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is sulfinyl or sulfonyl; mand n are each independently 0,1,2,3 or 4; and pharmaceuticallyacceptable salts thereof.
 21. A method of claim 19 or 20 wherein thenerve cell death or degeneration is caused by hypoxia, hypoglycemia,brain or spinal cord ischemia, retinal ischemia or brain or spinal cordtrauma.
 22. A method of treating a mammal suffering from or susceptibleto stroke, heart attack or brain or spinal cord trauma comprisingadministering to a mammal suffering from or susceptible to stroke, heartattack or brain or spinal cord trauma a therapeutically effective amountof a compound of the formula: ##STR46## wherein R and R¹ are eachindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted aminoalkyl, substituted orunsubstituted alkylsulfinyl or substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted carbocyclic aryl,substituted or unsubstituted aralkyl, or a substituted or unsubstitutedheteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8ring members in each ring and from 1 to 3 hetero atoms;each R² and eachR³ are each independently hydrogen, halogen, hydroxyl, azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is --O--, --S--, orsubstituted or unsubstituted --N--; m and n are each independently0,1,2,3 or 4; and pharmaceutically acceptable salts thereof.
 23. Amethod of treating a mammal suffering from or susceptible to stroke,heart attack or brain or spinal cord trauma comprising administering toa mammal suffering from or susceptible to stroke, heart attack or brainor spinal cord trauma a therapeutically effective amount of a compoundof the formula: ##STR47## wherein R and R¹ are each independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted aminoalkyl, substituted or unsubstitutedalkylsulfinyl or substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl,or a substituted or unsubstituted heteroaromatic or heteroalicyclicgroup having from 1 to 3 rings, 3 to 8 ring members in each ring andfrom 1 to 3 hetero atoms;each R² and each R³ are each independentlyhydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedaminoalkyl, substituted or unsubstituted carbocyclic aryl, orsubstituted or unsubstituted aralkyl having at least about 6 ring carbonatoms; X is sulfinyl or sulfonyl; m and n are each independently 0,1,2,3or 4; and pharmaceutically acceptable salts thereof.
 24. A method oftreating a mammal suffering from or susceptible to neuropathic pain,migraines, shingles, emesis, narcotic withdrawal symptoms or agecomprising administering to the mammal a therapeutically effectiveamount of a compound of the formula: ##STR48## wherein R and R¹ are eachindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted aminoalkyl, substituted orunsubstituted alkylsulfinyl or substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted carbocyclic aryl,substituted or unsubstituted aralkyl, or a substituted or unsubstitutedheteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8ring members in each ring and from 1 to 3 hetero atoms;each R² and eachR³ are each independently hydrogen, halogen, hydroxyl, azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is --O--, --S--, orsubstituted or unsubstituted --N--; m and n are each independently0,1,2,3 or 4; and pharmaceutically acceptable salts thereof.
 25. Amethod of treating a mammal suffering from or susceptible to neuropathicpain, migraines, shingles, emesis, narcotic withdrawal symptoms orage-dependent dementia, comprising administering to the mammal atherapeutically effective amount of a compound of the formula: ##STR49##wherein R and R¹ are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedaminoalkyl, substituted or unsubstituted alkylsulfinyl or substituted orunsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclicaryl, substituted or unsubstituted aralkyl, or a substituted orunsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3rings, 3 to 8 ring members in each ring and from 1 to 3 heteroatoms;each R² and each R³ are each independently hydrogen, halogen,hydroxyl, azido, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is sulfnyl or sulfonyl; mand n are each independently 0,1,2,3 or 4; and pharmaceuticallyacceptable salts thereof.
 26. A method of treating a mammal sufferingfrom or susceptible to decreased blood flow or nutrient supply toretinal tissue or optic nerve, or retinal ischemia or trauma, or opticnerve injury, comprising administering to the mammal a therapeuticallyeffective amount of a compound of the formula: ##STR50## wherein R andR¹ are each independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylthio, substituted or unsubstituted aminoalkyl,substituted or unsubstituted alkylsulfinyl or substituted orunsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclicaryl, substituted or unsubstituted aralkyl, or a substituted orunsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3rings, 3 to 8 ring members in each ring and from 1 to 3 heteroatoms;each R² and each R³ are each independently hydrogen, halogen,hydroxyl, azido, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is --O--, --S--, orsubstituted or unsubstituted --N--; m and n are each independently0,1,2,3 or 4; and pharmaceutically acceptable salts thereof.
 27. Amethod of treating a mammal suffering from or susceptible to decreasedblood flow or nutrient supply to retinal tissue or optic nerve, orretinal ischemia or trauma, or optic nerve injury, comprisingadministering to the mammal a therapeutically effective amount of acompound of the formula: ##STR51## wherein R and R¹ are eachindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted aminoalkyl, substituted orunsubstituted alkylsulfinyl or substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted carbocyclic aryl,substituted or unsubstituted aralkyl, or a substituted or unsubstitutedheteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8ring members in each ring and from 1 to 3 hetero atoms;each R² and eachR³ are each independently hydrogen, halogen, hydroxyl, azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is sulfinyl or sulfonyl; mand n are each independently 0,1,2,3 or 4; and pharmaceuticallyacceptable salts thereof.
 28. A method of treating a mammal sufferingfrom or susceptible to post-surgical neurological deficits orneurological deficits associated with cardiac arrest, comprisingadministering to the mammal a therapeutically effective amount of acompound of the formula: ##STR52## wherein R and R¹ are eachindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted aminoalkyl, substituted orunsubstituted alkylsulfinyl or substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted carbocyclic aryl,substituted or unsubstituted aralkyl, or a substituted or unsubstitutedheteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8ring members in each ring and from 1 to 3 hetero atoms;each R² and eachR³ are each independently hydrogen, halogen, hydroxyl, azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is --O--, --S--, orsubstituted or unsubstituted --N--; m and n are each independently0,1,2,3 or 4; and pharmaceutically acceptable salts thereof.
 29. Amethod of treating a mammal suffering from or susceptible topost-surgical neurological deficits or neurological deficits associatedwith cardiac arrest, comprising administering to the mammal atherapeutically effective amount of a compound of the formula: ##STR53##wherein R and R¹ are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedaminoalkyl, substituted or unsubstituted alkylsulfinyl or substituted orunsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclicaryl, substituted or unsubstituted aralkyl, or a substituted orunsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3rings, 3 to 8 ring members in each ring and from 1 to 3 heteroatoms;each R² and each R³ are each independently hydrogen, halogen,hydroxyl, azido, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkylhaving at least about 6 ring carbon atoms; X is sulfinyl or sulfonyl; mand n are each independently 0,1,2,3 or 4; and pharmaceuticallyacceptable salts thereof.
 30. A method of any one of claims 15, 17, 19,22, 24, 26, and 28 wherein the compoundis:N-(1-naphthyl)-4-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;N-(1-naphthyl)-4-(2,3-dihydro-[1,4]-benzoxazinyl)carboximidamide;N-(2,5-dibromophenyl)-4-(2,3-dihydro-6-trifluoromethyl-[1,4]-benzothiazinyl)carboximidamide;N-(2-fluoro-5-trifluoromethylphenyl)-4-(6-chloro-[1,4]-benzothiazinyl)-carboximidamide;N-(2,5-dibromophenyl)-4-(6-chloro-[1,4]-benzothiazinyl)carboximidamide;N-(1-naphthyl)-4-(6-chloro-2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;N-(5-acenaphthyl)-4-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;N-(2,3-difluorophenyl)-N-methyl-4-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;N-(1-naphthyl)-4-(6-trifluoromethyl-2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;N-(5,6,7,8-tetrahydro-1-naphthyl)-4-(2,3-dihydrobenzo-[1,4]-thiazinyl)carboximidamide;N-(3-biphenyl)-4-(2,3-dihydrobenzo-[1,4]-thiazinyl)carboximidamide;N-(2-naphthyl)-4-(2,3-dihydrobenzo-[1,4]-thiazinyl)carboximidamide;N-(3,5-dichlorophenyl)-4-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;andN-(2,3-difluoropbenyl)-4-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;ora pharmaceutically acceptable salt of said compounds.
 31. A method ofany one of claims 16, 18, 20, 23, 25, 27 and 29 wherein the compound isN-(2,5-dibromophenyl)-4-(2,3-dihydro-4-oxo-6-trifluoromethyl-[1,4]-benzothiazinyl)-carboximidamide;N-(2,5-dibromophenyl)-4-(2,3-dihydro-1-dioxo-6-trifluoromethyl)-([1,4]-benzothiazinyl)carboximidamide;orN-(1-naphthyl)-4-(2,3-dihydro-6-trifluoromethylbenzo[1,4]-1-oxo-thiazinyl)carboximidamide;ora pharmaceutically acceptable salt of said compounds.
 32. A method ofany one of claims 15-20, or 22-29 wherein R is substituted orunsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, ora substituted or unsubstituted heteroaromatic or heteroalicyclic group.33. A method of any one of claims 15-20 or 22-29 wherein R issubstituted or unsubstituted carbocyclic aryl.
 34. A method of any oneclaims 15-20 or 22-29 wherein R is substituted or unsubstituted phenylor naphthyl.
 35. A method of any one claims 15-20 or 22-29 wherein R isphenyl or naphthyl substituted at one or more ring positions by halogen,hydroxyl, azido, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, aminoalkyl, carbocyclic aryl, or aralkyl.36. A method of any one of claims 15-20 or 22-29 wherein R1 is hydrogenor substituted or unsubstituted alkyl.
 37. A method of claim 21 whereinR is substituted or unsubstituted carbocyclic aryl, substituted orunsubstituted aralkyl, or a substituted or unsubstituted heteroaromaticor heteroalicyclic group.
 38. A method of claim 21 wherein R issubstituted or unsubstituted carbocyclic aryl.
 39. A method of claim 21wherein R is substituted or unsubstituted phenyl or naphthyl.
 40. Amethod of claim 21 wherein the mammal is suffering from neuropathicpain.